JPH06507405A - Pyrrolidinones - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Pyrrolidinones field of invention The present invention provides novel pyrrolidinones, pharmaceutical compositions containing these compounds, and alleles. in the treatment of inflammatory and inflammatory diseases and the production of tumor necrosis factor (TNF). The present invention relates to the use of those compounds and compositions for inhibiting growth.

Background of the invention Bronchial asthma is characterized by reversible airway narrowing and hyperresponsiveness of the airways to external stimuli. It is a complex disease characterized by multiple factors.

Today, symptoms of chronic asthma include: 1) early response to antigen, 2) late or late response to antigen, and 3) It is recognized that chronic inflammation and airway hyperresponsiveness are manifestations of three distinct processes. There is. Cockcroft, Ann Allergy (^nn, Allergy) 55:857-862.1985; n), Hosp Practice (Bosp.

Practice) 22 +113-127. 1987° easily available Drugs (β-adrenocebuter agonists, steroids, methylxanthines, Thorium cromoglysate) is inadequate to control the disease, and the drug is The three stages of breathing should not be modified at all, and side effects should be limited for almost all drugs. No. Most importantly, with the possible exception of steroids, none of these drugs The goal is not to change the course of asthma.

Identification of new therapeutic agents for asthma has led to the understanding that multiple mediators are involved in the development of the disease. This is made difficult by the fact that Therefore, the effect of one mediator Elimination has a substantial effect on all three components of chronic asthma seems impossible. Another “mediator approach” is to The aim is to control the activity of cells involved in the pathophysiology of the disease.

One such method is cAMP (cyclic adenosine 3', 5'--phosphorus Cyclic AMP has a wide range of Secondary mechanisms that mediate biological responses to hormones, neurotransmitters, and drugs [Robison et al. Cyclic AMP Academic Press Press), New York, pp. 17-47, 1971; bs), Endocrinology Procedures of the Force I International Humbres Exerbuta Mezoica (Endocrino) logic Proceedings of the 4th International ional Congress■ Excerpta Medica), pp. 17-29, 1973]. proper chin When the drug binds to specific cell surface receptors, adenylate nucrase is activated. , it converts Mg''-ATP into cAMP at an accelerated rate. The action of cAMP is , hydrolyzes the 3°-phosphogesterase bond and produces an inactive metabolite, the 5′-A Termination by cyclic nucleotide phosphogesterase (PDE) to form MP. Complete.

Cyclic AMP contributes to the pathophysiology of extrinsic (allergic) asthma , regulates the activity of most, but not all, cells. The increase in cAMP is itself In the body: 1) Relaxation of airway smooth muscle, 2) Suppression of mast cell mediator release, 3) 4) suppression of basophil degranulation, and 5) monocyte and tumor suppression. Producing beneficial effects including inhibition of clophage activation. Thus, a Compounds that activate denylate cyclase or inhibit PDEs may be used to stabilize the airways. Effective in suppressing inappropriate activation of smooth muscle and a wide range of inflammatory cells.

The main cellular mechanism for cAMP inactivation is the cyclic nucleotide phosphogesin by a series of one or more isoenzymes called sterases (PDEs). It consists in the hydrolysis of 3°-phosphodiester bonds.

Cyclic nucleotide phosphogesterase (PDE) isoenzyme PDE IV is has been shown to be responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. 0 Torphy, New Drugs for As 7Phosphodi-esterase l5ozylI in thma es: Potential Targets for Novel Ant i-asthiatic@Agents''.

Barnes, ed. IBC Technical Services, Inc. 1989). Research shows that inhibiting this enzyme results in relaxation of airway smooth muscle. as well as suppression of monocyte and neutrophil activation, mast cells, basophils and This suggests that neutrophil degranulation is also suppressed. Furthermore, in vivo In some cases, the adenylate nucrase activity of target cells is inhibited by appropriate hormones or The beneficial effects of PDE TV inhibitors are significant when enhanced by It is greatly strengthened. Thus, prostaglandin E2 and prostacyclin ( adenylate cyclase activator), PDE TV inhibitors is effective in asthmatic lungs. Such compounds are used as drug therapy for bronchial asthma. It offers a unique approach to It also has significant therapeutic effects.

The compounds of the invention also inhibit the production of tumor necrosis factor (TNF), a serum glycoprotein. do. Excessive or uncontrolled TNF production can lead to rheumatoid arthritis, a rheumatoid arthritis. inflammation, osteoarthritis, gout arthritis and other arthritic conditions - sepsis, septic arthritis toxic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, adults Respiratory distress syndrome, cerebral malaria, chronic pneumonia disease, silicosis, pulmonary sarcoidosis, bone Absorption disease, reperfusion injury, graft-versus-host reaction, allograft rejection, influenza-like fever and myalgia due to bladder infections; cachexia secondary to infection or malignancy; Cachexia secondary to acquired immunodeficiency syndrome (AIDS), AIDS, ARC (AIDS-related keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis or involved in the mediation or aggravation of many diseases, including pyresis. There is.

TNF has been implicated in various roles in human acquired immunodeficiency syndrome (AIDS).

AIDS was caused by the human immunodeficiency virus (HIV) infection in 1923. It is. This time, we found that monokines, especially TNF, play a role in maintaining the activation of 1923 bulbs. It is related to the infection by HIV of 1923 bulbs by playing a role in was found. Furthermore, when activated T lymphocytes are infected with HIV, the 1923 The spheres remain activated and continue to carry out HIV gene expression and/or HIV replication. Let's go. In addition, monokines, especially TNF, have been shown to play a role in maintaining T lymphocyte activation. by playing a role in activated T cell-mediated HIV protein expression and/or It was also found to be involved in virus replication. Therefore, HIV-infected humans , monokines such as those by suppressing the production of monokines, especially TNF. Interfering with T cell activation may help limit maintenance of T cell activation, thereby reducing HIV infectivity. reduce the progression of cells to a previously uninfected cellular state, which is triggered by HIV infection. It slows down the progression or eliminates the immunodeficiency caused by the disease. Kutzpel cells and Monocytes, macrophages, and related cells such as glia also respond to HIV infection. related to maintenance. These cells, such as T cells, serve as markers for viral replication. and the level of viral replication depends on the activation state of the cell [Rosen et al. Rosenberg et al., The Immunovasogenesis of H. The Immunopathogenesis of HIV Infection), Atopanses in Immunology (^dvances in Immunology), Volume 57, (1989 ) Reference ko. Monokines such as TNF are present in monocytes and/or macrophages. has been shown to activate the HIV production [Poli et al. Dinges of the National Academy of Sciences (Proc. Natl, ^cad.

Jito), 87:782-784. (1990)], therefore monokine Suppression of production or activity may help limit the progression of HIV, as described above for T cells. to be accomplished.

Now we show that monokines have been linked to problems associated with certain diseases, such as cachexia and muscle degeneration. I found out that it's related. Therefore, in HIV-infected humans, TNF production Interfering with monokine activity, such as by suppressing blood flow, can lead to cachexia and muscle degeneration. by reducing the severity of problems associated with monokine-mediated diseases, such as It has been found to improve and support the standard of living of HIV-infected patients.

TNF has also been associated with yeast and fungal infections. In particular, candida Candida albicans is a human monocyte and natural killer. - Known to induce TNF production in vitro in cells [Lii Riipi et al., Infection and Immunity ion and Immunity), Volume 58.

No. 9: 2750-54 (1990); and Jafar i) et al., Journal of Infectious Diseases of Infectious Diseases), Volume 164 +389-95 See (1991). Additionally, Fasan et al. Le aging and chemotherapy (＾ntimicrobial Ag) ents and Chemotherapy); Volume 35, No. 10: 2046-48 (1991); and Luke et al., Journal Journal of Infectious Diseases ous Diseases), Vol. 162: pp. 211-214 (1990). light].

Knowledge of a series of compounds that control the production of TNF suggests that excessive or unregulated It would provide a method of treatment for diseases in which TNF production is implicated.

Summary of the invention The present invention includes benzylpyrrolidinone represented by formula (I) and these compounds. A pharmaceutical composition comprising:

The present invention further provides an effective amount of the compound of formula (1) for inhibiting phosphogesterase Phosphodisinfection in animals, including humans, consisting of administration to animals in need A method for inhibiting esterase is provided. Phosphogesterase ■ Inhibitors are used to treat asthma. , chronic bronchitis, atopic dermatitis, measles, allergic rhinitis, allergic Conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, chronic glomerulonephritis , a variety of allergic diseases including endotoxic shock and adult respiratory distress syndrome. and is useful in the treatment of inflammatory diseases. In addition, PDE IV inhibitors can be used to treat diabetes insipidus ( Kidney International (Kidney Int.) 37: 362 ．． 1990; Kidney International, 35:494, 1989), and multi-infarct dementia. It is useful in the treatment of central nervous system disorders such as ia).

The invention further requires an effective amount of a compound of formula (I) to inhibit TNF production. A method for inhibiting TNF production in animals, including humans, which comprises administering to animals provide law.

The present invention also provides an effective TNF-suppressing amount of a compound of formula (I) for human immunodeficiency virus. infection (HIV), AIDS-related complex (ARC), or other illnesses associated with HIV infection. relating to a method of treatment of a human being suffering from such a condition, which consists in administering the do.

The present invention further provides methods for treating humans by prophylactically administering an effective amount of a compound of formula 1. TNF-mediated pathologies in animals in need of prevention of TNF-mediated diseases, including It provides a method of prevention.

The compounds of the present invention also show that the virus is upregulated by TNF. regulation) or in vivo It is useful in the treatment of other viral infections that manifest production. In this specification The virus intended for treatment may be directly or indirectly treated with a TNF inhibitor of formula (I). directly, viruses that are susceptible to suppression, such as by reducing replication. Ru. Such viruses include, but are not limited to, HIV-L, HIV- 2 and HIV-3, cytomegalovirus (CMV), influenza, denoviruses, and viruses of the herpes group such as herpes zoster and herpes simplex. Contains viruses.

Compounds of formula 1 also show that yeast and fungi are susceptible to upregulation by TNF. Yeasts that are susceptible or exhibit TNF production in 10 vivo It is useful in the treatment of and fungal infections.

The preferred condition to treat is fungal meningitis. In addition, a compound of formula (I) Selected for systemic yeast and fungal infections with either simultaneous or sequential administration It may also be administered in combination with other drugs. Drugs of choice for fungal infections are referred to as polymyxins such as, but not limited to, polymycin B. A series of compounds including clotrimazole, econazole, miconazole and ketoco A series of compounds called imidazoles such as nazole, fluconazole and A series of compounds called triazoles, such as imidazoles, and amphoteric amphotericin B and liposomal amphotericin B. It includes a series of compounds.

Preferred microorganisms to treat are Candida organisms. Compounds of formula (I) have anti-viral It can be co-administered in a similar manner with antibacterial agents or antibacterial agents.

Compounds of formula (I) may also be used in combination with an effective amount of a compound of formula (I) as an antifungal, antibacterial or for mammals in need of suppressing and/or reducing the toxicity of antiviral agents. used to inhibit and/or reduce the toxicity of Good too. Preferably, the compound of formula (1) is a compound of the amphotericin type, especially amphotericin. Administered to suppress or reduce the toxicity of amphotericin B.

The compound of the present invention has the formula (1): [In the formula, R1 is C+-U, unsubstituted or substituted with one or more halogens; Alkyl, unsubstituted or substituted with 1 to 3 methyl groups or 1 ethyl group C3-6 cycloalkyl having 1 or 2 unsaturated bonds, C4-6 cycloalkyl having 1 or 2 unsaturated bonds Chloalkyl, C7-11 polycycloalkyl, (CRI4RI4)-C(0) O-(CRI4R14)-RI G, (CR14RI4)-C(0)O(CR1 4R14), R1+, (CRI4RI4), 0H1 (CR14R14), 0(C RI4R14)-R1゜, (CR14R14), 0(CRI4R14), R11 , (CRI4R14)-(C(0)NR14)(CRI4R14)-R1゜, ( CRI4R14), -(C(0)NH+4)(CR14R14), R1+, (C R14R14)-R1+ or (CR14R14), RIG; X is 0 or S: Xl is O* or NR, 4° X is hydrogen or X: X is YR, halogen, nitro, NRI4Rl4 or formamide; Y is O or 5(0)+a; R2 is -CH, or -CH, CH, each of which is unsubstituted or 1- May be substituted with 5 fluorines: R5 is hydrogen, halogen, CN, Cl-4 alkyl, halo-substituted C1-4 alkyl, Cyclopropyl, OR6, -CH20, unsubstituted or substituted by Ro R5, N Rs R1a, -CH2N Rs R1e, -C(0)ORs, C( 0) NR6R16, -CH=CRs Re, C=CR* or -C (=Z) It's H.

R1' is hydrogen, halogen, C7-4 alkyl, halo-substituted C1-, alkyl, unsubstituted cyclopropyl, -CH20R5, CH2N substituted with Rs R+ a, -C(0)OR,,C(0)NRsR1s or -C(=Z )H; A is or (C) unsubstituted or one or more fluorine or one or two R4 groups; C1-3 alkyl substituted by.

m is an integer from 0 to 2.

n is an integer from 1 to 4: q is an integer between O and 1.

r is an integer from 1 to 2.

S is an integer from 2 to 4; X is an integer from 2 to 6; y is an integer from 1 to 6; 2 is an integer from 0 to 6; R4 is independently hydrogen, Br, F, C1, N Rs Rs, N Rs Rr a, NO3, -C(Z)R,, 5(0)-RI2, CN, 0RI8 0C(0) NR6R16, 1- or 2-imidazolyl, -C (= N R + s) N Rs RI*, -C (=NRs) SRu, -〇C (0) CH3, C (=NC N) NRsRu, -C(S)NR6R16, NR+a-C(0)RI 5, C( 0) R+s, oxacylyl, thiazolyl, pyrazolyl, triazolyl or tet lazolyl: or when R5 and RI6 are NR5R,g, the nitrogen together with the element, at least one selected from 0, N, or S, as desired may form a 5- to 7-membered ring which may contain an additional petero atom; R 5 is independently hydrogen or unsubstituted or substituted with 1 to 3 fluorines is C1-4 alkyl; R8 is H, RI2, -C(0) Rl2, -C(0)C(0)R,,C(0 ) N Rs Rle, -8 (0), Ru, -5 (0), CF3, C (= N CN) S R+ 2, -C (= N CN) R+ 2, -C (= NR4s) Ru, C (= N R + s) S R + t or -C (= N　CN　　N　Rs　Rr　s.

R7 is OR5, -N Rs R+ s or R32: R8 is hydrogen, C(0)R7 , (2-14- or 5-imidazolyl), (3-14- or 5-pyrazolyl ), (4- or 5-triazolyl-[1,2,3]), (3- or 5-triazolyl-[1,2,3]) Azolyl-[1,2,4-), (5-tetrazolyl), (2-14- or 5- Oxacylyl L (3-14- or 5-isoxacylyl), (3- or 5- Oxadiazolyl [1,2,4]), (2-oxadiazolyl [1°3.41) , (2-thiadiazolyl[1,3,4]), (2-14- or 5-thiazolyl ), (2-14- or 5-oxazolidinyl), (2-14- or 5-thia (zolidinyl) or (2-14- or 5-imidazolidinyl); R8 is Hydrogen, F or R12゜ Rl　O is hydrogen, methyl, hydroxy, aryl, halo-substituted aryl, aryl Oxy C1-3 alkyl, halo substituted aryloxy C1-, alkyl, indani ru, indenyl, C7-11 polycycloalkyl, furan, bilane, thiophene , thiobilane, C8-6 cycloalkyl, or one or two unsaturated bonds C4-6 cycloalkyl with unsubstituted or substituted with 1 to 3 methyl groups or 1 ethyl group R1+ may be unsubstituted or 1 to 3 methyl groups or 1 ethyl group; 2-tetrahydrobilane, 2-tetrahydrothioviran substituted with 2-tetrahydrofuran or 2-tetrahydrothiophene: Rl 2 is O3-4 alkyl which is unsubstituted or substituted with 1 to 3 fluorines; the law of nature.

R14 is independently hydrogen or C unsubstituted or substituted with fluorine; 1. □2 alkyl: R15 is unsubstituted or substituted with one or more halogens Cl-4 alkyl, unsubstituted or substituted with one or more halogens ( 0) C1,4 alkyl, oxazolidinyl, oxasilyl, thiazolyl, pyrazo Lyle, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazo Lysinyl, isoxasilyl, oxadiazolyl, thianazolyl, morpholini , piperidinyl, piperazinyl or pyrrolyl, each of which is Even if it is unsubstituted or substituted with 1 or 2 01-2 alkyl groups often.

R, 6 is OR, or R5゜ Z is O, -NRI2, -N ORs, NCN, N(-CN)2, CRs N O2, -CR5C(0)OR+2, CRs C(0) N Rs Rs, - C(-CN)NO2, -C(CN)C(0)ORu or -C(CN)C( 0) N Rs means Rs; however, (CR14R+4), -C(0)O -(CR14R,4), -R1゜, (CR14R14)-1(C(0)NR14 )(CR14R14)-R+a or fi(CR14R14), 0(CRuR,+ 4) --Ro. When R1゜ in the middle is OH, m is 2, and furthermore, q is 0 , R3, R3゛, Ra and Xs force'HTAl), x is OR2, and x 2 is O and xI is.

or S, the least of the R4 or R34 groups in (a) or (b) At least one is a group other than hydrogen] or a pharmaceutically acceptable salt thereof.

Also encompassed by the present invention are pharmaceutically acceptable salt-extracting combinations of the compounds of the present invention that are capable of forming salts. be done.

All defined alkyl groups may be either straight chain or branched.

The compounds of the invention may contain one or more asymmetric carbon atoms, and may contain one or more asymmetric carbon atoms. They may exist in optically active and optically active forms. All of these compounds are in accordance with the present invention. Included within the scope of. The term "halogen" means chloro, fluoro, bromo or Used to mean iodine. The alkyl group can be mono or perhalogenated. may be substituted with more halogens.

As used herein, the term "cycloalkyl" refers to cyclopropyl, cyclopropyl, A group having 3 to 6 carbon atoms such as pyrumethyl, cyclopentyl or cyclohexyl include.

As used herein, the term "aryl" or "aralkyl" is used unless otherwise specified. 6 to 10 carbon atoms, such as phenyl, benzyl, phenethyl or naphthyl means an aromatic ring or a scientific system. Preferably, aryl is a monocyclic ring, i.e. It is henyl.

C7-11 polychloroalkyl is, for example, bicyclo[2,2,1]hebutyl, Bicyclo[2,2,2]octyl, Vinclo[3,2,1cooctyl, Tricycyl Includes ro [5, 2, 1° 02° 6] Denru, etc. Saccam WO 37106576, published November 5, 1987, by Examples are described, the disclosure of which is hereby incorporated by reference.

N　Rs　R+　R5 and RI6 in the a group are the nitrogens to which they are bonded together with, if desired, at least one selected from O/N/ and S to form a 5-7 membered ring which may contain further heteroatoms of Examples include, but are not limited to, 1-imidazolyl, 1-pyrazolyl, 1- Triazolyl, 2-triazolyl, tetrazolyl, 2-tetrazolyl, morpholyl Nyl, piperazinyl or pyrrolyl rings.

Furthermore, the present invention provides novel pharmaceutical compositions of compounds of formula I.

The present invention provides for administering a compound of formula (I) to a subject in need of suppression of PDE IV. The present invention provides a method for suppressing the above.

The present invention further provides an effective amount of a compound of formula (I) for treating allergic and inflammatory diseases. Proposes a method of treating a disease, which comprises administering the disease to a subject in need thereof. The invention also provides for administering an effective amount of a compound of formula (I) to a subject in need of treatment for asthma. Provided is a method for treating the disease, which comprises:

Compounds of formula (I) may be exacerbated or precipitated by excessive or unregulated TNF production. useful for prophylactically or therapeutically treating pathological conditions in humans that occur. Ru.

Therefore, the present invention also provides an effective amount of a compound of formula 1 to suppress the production of tumor necrosis factor. such animals, including humans, consisting of administration to animals in need of control; Provided are methods for inhibiting tumor necrosis factor (TNF) production in patients.

The term “inhibition of rTNF production” means a) All cells including but not limited to monocytes or macrophages 1 in humans by inhibiting the in vivo release of TNF by cells. Reducing excessive TNF levels in vivo to normal or below normal levels To do.

b) Excessive TNF levels in humans at the translational or transcriptional level or C) post-translational As an event, it means downregulation by suppressing the direct synthesis of TNF.

The term "rTNF-mediated disease" refers to diseases caused by or limited to the production of TNF itself. However, other substances released due to TNF, such as IL-1 or IL-6, By itokine we mean all pathological conditions in which TNF plays a role. However, For example, IL-1 is the main component, and its production or action is intensified. or pathological conditions in which IL-1 is secreted in response to TNF. It is thought that this is a disease state that is mediated by

As used herein, the term "cytokine" refers to cytokines that affect the functions of other cells. , any fraction that is a molecule that modulates interactions between cells in immune or inflammatory responses. Also refers to secreted polypeptides. Cytokines include, but are not limited to, Regardless of whether the cells in question produced monokine and lymphocytes, the Contains matter. For example, monokines generally target macrophages and/or is said to be produced and secreted by mononuclear cells such as monocytes, but Natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow base Numerous other cells such as plasma cells, epidermal keratinocytes, and β-lymphocytes are also monocytogenes. Produces cain. Lymph cells are generally produced by lymphocytes. It is said that Cytokines for the present invention include, but are not limited to: However, interleukin-1 (IL-1) and interleukin-6 (IL -6), tumor necrosis factor-α (TNFα) and tumor necrosis factor-β (TNFβ) A preferred subgroup of compounds of subgroup (I) is represented by formula (Ib): [wherein, R1 is C unsubstituted or substituted with 1 to 3 methyl or ethyl groups, -C6 cycloalkyl, C unsubstituted or substituted by 1 to 3 fluorines 1-, alkyl, (CH2)-C(0)O-(CHz), CHs, -(CHri , 0(C1h), -CH3, -(CH,)+OH, -CH2-shi'yo bench # , -CH2-Sifopropyl or 3-tetrahydrofuranyl; X is -Y R,, halogen, nitro, amine, Cl-2 dialkylamine, Cl-2 monoa rukylamine or formylamine; Y is 0 or 5(0); R7 is -CH3 or -CH2CHs, each of which is unsubstituted or 1- It may be substituted with 4 fluorines (; R3 is hydrogen, CH3, CN, F, OH, -CiiCRs or CFs: 1 is 0 or S: q is O or 1° R4 is independently hydrogen, Br5F, C1, -NRsR+s, NO2, -C( Z) Rt, 5(0), Cl-3 alkyl, CN, OR+s, -QC(0)NR aRta, 1- or 2-imidazolyl, C(=NR+a)NRsR+. ,-C (=NRs) SR+z, -C(0)R15,70C(0)CH3,C(=N CN) N Rs R+e, -C(S) N Rs RIg or NH C(0)Rts: R3 is independently hydrogen or unsubstituted or substituted with 1 to 3 fluorines; is C1-4 alkyl; R6 is HSR, 2, C(0)Rtz, -C(0)C(0)R7, C(0)N Rs RIb, 5(0)-CR12,-3(0),,CF8,-C(=N CN) S R+ 2, C(=NCN)NRsRI6, C(=NCN)R 12 or -C(=NR+a)Rt2: Rd;! ORs, NRsR+e *or Rt2; R is hydrogen or -C(0)R; R9 is hydrogen, F or R12; RIB is Cl-4 alkyl, unsubstituted or substituted with 1 to 3 fluorines; And; Rt4 is hydrogen or unsubstituted or substituted with one or more fluorine is Cl-Z alkyl; RIB is Cl-4 unsubstituted or substituted with one or more halogens Alkyl, unsubstituted or substituted with one or more halogens -C( 0) Cl-4 alkyl, oxazolidinyl, oxasilyl, thiazolyl, pyrazo Lyle, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazo Lysinyl, isoxasilyl, oxadiazolyl, thiadiazolyl, morpholini , piperidinyl, piperazinyl or pyrrolyl, and each subsequent ring is Unsubstituted or substituted with 1 or 2 C1-, alkyl groups Compounds represented by: R111 means OR or R6 or pharmaceuticals thereof It is a pharmaceutically acceptable salt.

Preferred compounds are those in which R1 is CH,-cyclopropyl, CH,-C,, cycloal Kyl, C4-6 cycloalkyl, tetrahydrofuranyl, cyclopentenyl, C optionally substituted with one or more fluorine or chlorine l-7 alkyl or -(CHI)2-40H, and XI and X2 are oxygen , X is YR2, Y is oxygen, and R2 is optionally one or more halide C1-2 alkyl optionally substituted with fluorine, preferably fluorine or chlorine , one of Rs is hydrogen, the other of R1 is hydrogen, C=cRI, CN, C (=Z)H, CHIOHSCH2F1CH2Ht or cFs, and Z is 01N CN or N0Rs"C' is present, R3" is hydrogen, X3 is hydrogen, and A is (a), R4 is H, Br, 0R4s, CN5NRsRs, NO7, C(0 ) R7,5(0)-Rtz, 1- or 2-imidazolyl, -QC(0)CH 3 or NHC(0)R+s, and R8 is C(0)OHSH or C( 0) OEtT a-, te, R+J' hydrogen, CHs, NHJ? : is NHc(0)CH sT is a certain compound. − Further preferred compounds are those in which R, is substituted by one or more fluorine. C1-4 alkyl, CHI-cyclopropyl, CH,-cyclopentyl, cyclo Lopentyl or cyclopentenyl, R8 is methyl or fluoro substituted C trialkyl, R8 is hydrogen, C=CH or CN, and R4 is hydrogen , Br, NH*, -NHC(0)CH,, C(0)OH, -NHC(NCN)S CH3, NHC(0) NHt, -N(CHs)*, NHC(0)C(0) OCHs, -NHC(0)C(0)OH,NH3(0)2CH3, -C(0) OCHs, 5(0)zcHs, 5cHs, -NHC(0)C(0)CHI, 5( 0)CH8, -NHC(0)C(0)NH,,CN.

C(0)NH,,NH3(0)ICF! , C(NH)NH2,0-C(0)cH t, -CCO)N (CHs)! , 1- or 2-imidazolyl, -NHC (0)CHtCl, -NHC(0)-oxazolidinyl, -NHC(0)-4, A compound that is 4-dimethyloxazolidinyl or OH.

The most preferred compounds are those in which R1 is cyclopentyl, CF, CHIFSCHFz, CF! CHF 2, CH2CHF, CH2CHF2, CH3, CH2-Sik Lopentyl, CH, -cyclopropyl or cyclopentenyl, and R1 is C F3, CHF, or CH, CHF, where one of R8 is hydrogen and the other of R3 is hydrogen, C=CH or CN in the 4-position, one of R4 is hydrogen and the other is -NHC(0)CH3,NH2,NH-C(=NCN)SCH,,NHC(0 )CO2CH3, C(0)OCHs, NHC(0)NH2, NHC(0)C(0 )CHst or NHC(0)C(0)NH2t) or both R4 groups are NH2 or NHC(0)CH, where R1 is hydrogen and R24 is hydrogen. It is a certain compound.

Particularly preferred compounds are listed below. 1-(4-aminobenzyl)-4-(3-cyclopentyloxy-4-methoxy phenyl)-2-pyrrolidinone.

1-(4-acetamidobenzyl)-4-(3-cyclopentyloxy-4-methyl quinphenyl)-2-pyrrolidone; 1-(4-oxamidobenzyl)-4-(3-cyclopentyloxy-4-meth xyphenyl)-2-pyrrolidinone; 4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(2,4-di acetamidobenzyl)-2-pyrrolidinone; 4-(3-cyclopentyloxy) -4-methoxyphenyl)-1-(2,4-diaminobenzyl)-2-pyrrolidi Non; 1-(4-carbomethoxybenzyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-2-pyrrolidone: 4-(3-cyclopentyloxy-4- methoxyphenyl)-1-(4-N”-[N~2-cyano-8-methylisothi [ouraid]benzyl)-2-pyrrolidinone; 1-(4-N-carbomethoxyca rubamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl )-2-pyrrolidone; 4-(3-cyclopentyloxy-4-methoxyphenyl )-1-(4-N-[ureido]benzyl)-2-pyrrolidone; and 4-(3 -Fuclopentyloxy-4-methoxyphenyl)-1-(4-bilbamideben zyl)-2-pyrrolidinone.

Particularly the most preferred compounds are: (S)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-2-pyrrolidinone; (R)-1-(4-acetamidoben Zyl)-4-(3-cyclobentyloxy-4-methquinphenyl)-2-pyro Lysinone; (S)-1-(4-acetamidobenzyl)-4-(3-cyclopene methyloxy-4-methoxyphenyl)-2-pyrrolidone.

General synthesis method Compounds of formula (Ia) can be prepared by the following procedure: a) R, power , RI2 or unsubstituted or substituted with R8, X and X is 5 (0), R2 (where m is 1 or 2), BrXL NO2 or or a group other than formylamine, in the case of a compound having the formula (2) [wherein, X 2 R +, X and X3 are respectively X2R11x and X defined in formula (I), or a group that can be converted into X2R, , X and X3, , means H] The compound represented by is prepared in a suitable solvent such as benzene or toluene at reflux temperature. and a suitable catalyst (e.g. titanium tetrachloride or a quaternary amine base) together with the acid. in an inert atmosphere with or without water removal) and/or with azeotropic removal of water. React with a suitable malonate ester derivative such as trimethyl malonate under an ambient atmosphere. (3) The compound represented by (R1, is an alkyl or aryl group, and R18 is COO R + 7) is obtained. 25-90°C in a suitable solvent such as aqueous alcohol Then, the compound of formula (3) is replaced with sodium cyanide, potassium or tetraalkyl cyanide. By reacting with a cyanide source such as ammonium, formula (4): or C0OR, □] is obtained.

Alternatively, a compound of formula (2) may be added to, for example, carbalcoquine- or carboalcoquine- Reacts with lyloxy-methylenetrialkyl- or triarylphosphorane. Then, a compound of formula (3) (R18 is H) is obtained. A suitable solution such as aqueous alcohol The compound of formula (3) is added to sodium noanide, potassium or or a cyanide source such as tetraalkylammonium, further converting the formula ( Compound 4) (H3' is H) is obtained.

In addition, the compound of formula (3) (R18 is H) can be prepared from nitromethane produced from an appropriate base. anion, or alkoxide, tetraalkylguanidine or halogen. In the presence of a suitable catalyst such as quaternary ammonium The reaction is carried out in a suitable solvent such as methane, and the formula (5)-[wherein R3' is COOR An ester compound represented by +□ was obtained, and it was hydrolyzed and decarboxylated. The compound of formula (5) (R3' is H) is obtained by xylation. Similarly, the compound of formula (5) The compound (R8' is H) is obtained by first adding 1) the compound of formula (2) to nitromethane as described above. React with formula (6): 2) The compound of formula (6) was obtained in a suitable solvent ( (e.g., tetrahydrofuran) at a suitable temperature (e.g. -78°C). Bases (e.g. lithium diisopropylamide or lithium hexamethyldisilamide) alkyl or aryl acetate anions produced using It may also be induced by reacting.

Also, R7o is H, and R3 is H, R12, unsubstituted or substituted with R. A compound of formula (9) (described below), which is noclopropyl, is reacted with a strong base. followed by a suitable alkyl or aryl compound such as methyl α-bromoacetate. Reaction with α-halocarboxylate also allows R3 to be H, R, 2 or unsubstituted. Alternatively, a compound of formula (4) which is cyclopropyl substituted by R8 is obtained. It will be done.

reducing the nitrile group of the compound of formula (4), or a similar compound of formula (5) By reducing the nitro group of the compound, the formula (7) is obtained.

"In the formula, RI9 is a symbol that means H. The compound shown is obtained. The amine (R1, is H) of formula (7) is replaced with chloroform. The imine is then reacted with the aldehyde at reflux temperature in a suitable solvent such as For example, reduction with sodium cyanoborohydride in methanol in the presence of acid. , obtain a compound of formula (7) (R, e are OH2(CHt), A); Then, the compound of formula (7) is cyclized to obtain the corresponding compound of formula (Ia). . Alternatively, a compound of formula (7) (R+s is H) is prepared with a catalyst in a suitable solvent. with or without a suitable activated alkali such as a halide, mesylate or tosylate. When reacted with a killing agent, the compound of formula (7) 17) (Ru is CHRa(0)-(C H2), ATa6)'lr: the corresponding compound of formula (Ia) as described above May be cyclized into objects. In addition, the compound of formula (7) (R1, is H) is cyclized. , Formula (8) [In the formula, RH means H] A suitable compound of formula (8) (R1, is H) was added to sodium hydride. The amide anion is then reacted with a strong base such as halium. by reacting with a suitable active alkylating agent, such as di-, menlate or tonlate. A compound of formula (Ia) is also obtained.

b) R3 is CN, X and X3 are 5 (0), Rz (m is 1 or 2) , Br.

In the case of a compound that is a group other than L No2 or formylamine, a compound of formula (2) (Rs is H) is reacted with lithium halide and silyl halide in a suitable solvent. reaction, followed by reduction with a suitable reducing agent such as siloxane, formula (9): , X4 is chloro or bromo, R3 and R2O are Alternatively, the compound of formula (2) (R3 is H) may be prepared using, for example, methanol. The compound of formula (9) (X4 is OH) was reduced with sodium phosphide hydride.

R3 and R2° are H), which can be treated, for example, with phosphorus trichloride, thionyl chloride, trichloride, etc. Reacts with phosphorus bromide, cupric bromide or carbon tetrabromide and triphenylphosphine and further compound of formula (9) (X4 is chloro or bromo, R3 and R 20 obtains H). Then, by replacing the halide with ananido, a compound of formula (9) is obtained. (X is CN, R3 and R2° are H), and the compound was prepared under an inert atmosphere at low temperature. reaction with a strong base such as butyl lithium at room temperature and then a) e.g. treated with magnesium and subsequently reacted with e.g. trimethylsilyl isocyanate. The compound of formula (9) (R3 is CONH2, R2o1; LH, X4 is CN) or b) a haloformic acid such as methyl chloroformate. A compound of formula (9) (R3 is COORIt, R20 is H, X4 is CN): The COOR, □ group of such a compound is At this stage or at some later stage, react with concentrated ammonium hydroxide. Furthermore, it can be transformed into 82 C0N groups using conventional means in the field.

Alternatively, a compound of formula (9) (Rs is C0OR+t, R4o is H, X41tC N) can also be used to convert the compound of formula (9) (Rs and R1° are H, X4 is CN) to carbon Sodium hydride in the presence of a dialkyl or diaryl carbonate such as dimethyl acid It can be obtained by reacting with a metal hydride such as aluminum. Also, this A compound of formula (2) (Rs is C0OR+t, X< and Rxo liH) with methyl methyl sulfinyl methyl sulfide and a base such as water. Species such as those reacted with sodium oxide and subsequently treated with e.g. alcoholic acid. A compound of formula (9) (R3 is C0OR, , X4 and R8 ° can be obtained by homologizing to H). This kind of equation (9) The anion of the compound is generated using a suitable base, followed by e.g. cyanogen chloride. Alternatively, the compound of formula (9) (R3 is C0OR, □, R2° is H, and X4 is CN). An appropriate base in an appropriate solvent using the compound of formula (9) (R1 is H, X4 is CN, Rs is C0NHz or C00Ru) to produce 7-one, followed by alkyl α-halocarboxylate or is reacted with aryl to form a compound of formula (4) (Rs is C0NHz or C0OR+ t); The compound of formula (7) (R1, is HSR, is C 0NH or COOR+? ) is obtained. Then, the compound of formula (7) (R+ e is H, R3 is C0NHz) to protect the amine part of the compound of formula (7) (R+o is protecting group such as t-butyloxycarbonyl group, R3 is C0NHt); The mido can be dehydrated, for example with trifluoroacetic anhydride, followed by removal of the protecting groups to form the formula The compound of (7) (R3, is H, R3 is CN) is obtained, and then the compound is converted to the formula (7). As described above for other compounds of formula (Ia) (R, is CN).

X and X3 are S(ORR, (m is 1 or 2), Br, L NOx or hol may be transformed into a group other than lumylamine).

C) R3 in formula (I) is OR or F, X and X are 5(0), Rz (m is 1 or 2), BrS I, Now or a group other than formylamine Compounds that convert their hydroxyl groups into silyl ethers, acetals or esters , starting with a suitably protected cyanohydrin, e.g. t-BOC. It is produced according to the reaction of Compound of formula (2) (Rs is H, Ru or unsubstituted or cyclopropyl substituted with Ro) is treated with a hydrocyanic acid derivative. , obtain cyanohydrin of formula (9) (Rs is H, Rso is 0HSX, is CN) . The compound of formula (9) is treated with a suitable protecting agent such as trimethylsilyl chloride, di-t- Work-up with butyl dicarponate and appropriate base or methyl vinyl ether Alternatively, the compound of formula (2) can be combined with trimethylsilyl cyanide and a Lewis acid. directly treated with protected cyanohydrin of formula (9) (Rs is HSR2o is protected hydro xyl, X4 is CN).

The protected cyanohydrin is treated with a strongly hindered base, e.g. After treatment with iLDA and subsequent reaction with e.g. Upon treatment, a compound of formula (4) (Rs is a protected hydroxyl, R3° is H) is obtained. child For example, by hydrogenating the nitrile group of a compound with a Ranini-Nokel catalyst, The compound of formula (7) (R3, where HSRa is a protected or unprotected hydroxyl) sil). These compounds of formula (7) were alkylated on nitrogen and treated as described above. and then treated with diethylaminosulfur trifluoride to form a compound of formula (Ia) ( RsliF) is obtained.

d) Compound of formula (Ia) (R means the remaining R3 group of formula (Ia)) 1 mer , from the compound of formula (8) or formula (Ia) (Rs is CN), amides and other Protect highly reactive functional groups, for example, reduce the CN group of R3 to CHO1, and Transform the functional group of CHO under any of the standard conditions well known in the field. can be derivatized according to the manipulation of the CN functional group.

Some of the compounds of formula (Ia) are A, X, Kari, Xz R1, R8? : f;! By appropriate manipulation of the functional groups present in or such the Rs' group, Prepared from another compound of formula (Ia).

The compound of formula (Ia) (R3 is CF s, CHF 2 or CH, F) is may be prepared from the corresponding compound of formula (2) using a method. The compound of formula (2) ( R3tiC,F3) is published by Noyova5hono) et al., Journal of Ogre Ni Tsuku Chemistry (J, Org, Chem,), Volume 56, Page 204 (1 991) from the compound of formula (2) (Rs is H). Ru.

The compound of formula (2) (Rs is CF or CF!H) is a compound of formula (10): , Nad et al., Izvest, (1959) p. 71 ;Chemical Abstracts (Chew, ^bstr, ) Volume 53, No. 1 -7 by the method of Volume 4977; and Volume 53, No. 17933 (1959) Treatment with a metallizing agent followed by trifluoroacetic acid or difluoroacetic acid at 8°C. It is obtained by

The compound of formula (2) (Rs is CH2F) is synthesized by Rozen et al. Synthesis (6) 665. (1985) method , obtained by treating the compound of formula (2) (R3 is CH3).

X is 5 (0), R,! and m is 1 or 2, the final compound After dehydrating the appropriate C0N82 group in the synthetic route to a cyano group, (by oxidizing the intermediate -SR+z product under known conditions) by those skilled in the art. is produced from the -3R,2 group. X and/or X3 is Br, I, nitro , for compounds that are amines or formylamines, the synthesis of these compounds is Amines appropriately protected as X and/or X3 by any of the above steps This is achieved using Such protecting groups are known to those skilled in the art. Greene, T., Protecting Groups in Organic Synthesis (Protective Groups in Organic 5ynthes is), Wiley Publishers, NY ( 1981). The contents thereof are hereby incorporated by reference. . The deprotected amine is then optionally acylated to a formylamine group, or oxidized to NO2 groups or diazotized and converted to C by methods well known to those skilled in the art. Obtain the desired Br or one group.

Both functional groups were manipulated and protected as appropriate and described in the Methods and Experimental section above. The remaining compounds of formula (I) are synthesized according to methods analogous to those described. be able to.

Compounds of formula (1) or pharmaceutically acceptable compounds thereof for the treatment of humans and other mammals For use in salts, the compounds are typically formulated into pharmaceutical compositions according to standard pharmaceutical procedures. It is prescribed as

Compounds of formula (I) and their pharmaceutically acceptable salts are standard compounds for the treatment of indicated diseases. For example, orally, parenterally, sublingually, transdermally, rectally, by inhalation or by injection. It can be administered by oral administration.

Colored compounds of formula (1) that are active when administered orally and pharmaceutically acceptable salts thereof can be formulated as syrups, tablets, capsules and lozenges. syrup formulation Generally, liquid carriers such as ethanol, peanut oil, olive oil, glycerin A suspension or suspension of the compound or salt, including flavoring or coloring agents, in water or water. or a solution. When the composition is in tablet form, it is customary to produce solid dosage forms. Other pharmaceutical carriers can also be used. Examples of such carriers include: contains magnesium stearate, clay, talc, gelatin, agar, pectin, aluminum Contains Kanoa, stearic acid, starch, lactose and sucrose. set When the composition is in capsule form, for example, the above-mentioned Any conventional encapsulation procedure using a carrier is suitable. The composition is soft gelatin When in the form of shell capsules, it is customary to make dispersions or suspensions. Any pharmaceutical carrier used in Or oils are also contemplated and can be incorporated into the soft gelatin capsule shell.

Typical parenteral compositions optionally include a parenterally acceptable oil, such as polyester. Ethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil A solution of the compound or salt in a sterile aqueous or non-aqueous carrier which may contain or Consists of a turbid liquid.

Typical inhalable compositions include solutions, suspensions or sesame seeds that can be administered as dry powders. dichlorodifluoromethane or trichlorofluoromethane. It is in the form of an aerosol using a conventional propellant such as fluoromethane.

Typical galenic preparations contain compounds of formula (I) that are active when administered in this manner. or a pharmaceutically acceptable salt thereof, and a binder and/or lubricant, such as a polyester. Marglycol, gelatin, cocoa butter or other low melting point vegetable oils or mixtures and analogues.

Typical transdermal formulations include conventional aqueous or non-aqueous vehicles, such as creams, soft consisting of a salves, lotions or bases, or medicated plasters, patches or or in the form of a membrane.

Preferably, the composition is in the form of tablets, capsules, etc. so that a single patient can administer a single dose. It is in unit dosage form in cells or metered aerosol doses.

Dosage units for oral administration each suitably contain 0.001-100 mg/kg, preferably Preferably, each dosage unit for parenteral administration contains 0.01 to 30 mg/kg. , a compound of formula (i) or a pharmaceutically acceptable salt thereof, calculated as free base, Suitably, it contains 0001 to 40 rng/kg. For nasal administration or oral inhalation The dosage unit is suitably 1 to 400 mg, preferably 10 to 2 mg per person, respectively. Contains 9mg. Topical formulations suitably contain from 0.001 to 1.0% of a compound of formula (I). Contain something. Dosage units for rectal administration each suitably contain from 0.01 mg to 10 mg. Contains 0 mg of compound of formula (I).

For oral administration, the dose of -(1) is suitably expressed as the free base and converted to the formula ( The compound of 1) or a pharmaceutically acceptable salt thereof is about 0.01 mg/kg to 40 m g/kg. Daily dose resins for parenteral administration are suitably formulated as free bases. The compound of formula (I) or a pharmaceutically acceptable salt thereof is approximately 0.001 m g/kg ~ 40mg/kg, for example, about 0.001mg/kg - 40mg/k It is g. The daily dosage resin for nasal administration and oral inhalation suitably contains about 10 ~about 1200 mg/person. Take the active ingredient 1 to 6 times a day to show its anti-inflammatory activity. When administered in sufficient doses or when used as a TNF inhibitor, it may improve symptoms. normal or below normal levels are achieved that are sufficient to prevent or The active ingredient is administered in an amount sufficient to suppress TNF production.

The biological activity of compounds of formula I as PDE IV inhibitors was determined by the following test procedure. Measure again.

Inhibitory effect of compounds of formula I on PDE TV 1, isolation of PDE isoenzyme The phosphogesterase inhibitory activity and selectivity of the compounds was determined using a group of five different PDs. Measured using E isoenzyme. The properties of these PDEs are shown in Table 1. various iso The tissues used as sources of enzymes are as follows: 1) PDE Ia.

Dog tracheal muscle; 2) PDE Ib, porcine aorta; 3) PDE Ic, guinea pig 4) PDE II[, guinea pig heart; and 5) PDE IV, human monocytes. PDEIa, Ib, Ic and ■ were analyzed using standard chromatography. - Partial purification using techniques (Torph and Sheslinsky) y and C1eslinski), Molecular Fur7co01o1 ．． Pharmacol, ) 37: 206-214.1990). P.D. E IV, anion exchange followed by heparin-sepharose chromatography Purify to kinetic homogeneity by a series of uses of Torphy et al., Journal of Biological Chemistry (J,B iol, Chem, ), 267: 1798-1804 (19 peaks Enzyme Km (mM) cAMP cGMP Ia cGMP-specific 135 4 Ib Ca”/calmodulin-stimulation 50 5Ic, Ca24/calmo Nyurin-stimulation 12m cGMP-inhibition 0.48 rV Ro20-1724-Suppression 4 38a Data are from Torfi and She Names from Slinsky (cited above) are Beavo, Adv, 5econd Messenger phosphogesterase activity in Torphi and Siesrin Key, Molecular Fur 7 Co0G 37:206-214.1990. Assayed according to. For compounds of the present invention, IC nos range from 25 μM to 50 μM. It is in the range of 0 μM.

I [[, cAMP accumulation in U-937 cells in intact tissues, selected PDEs I The ability of V inhibitor to increase cAMP accumulation was demonstrated in U-937 cells, which contain a large amount of PDE rV. The evaluation will be performed using a human monocyte cell line known to be effective. PD in intact cells To evaluate the ability to suppress E.IV, undifferentiated U-937 cells (approximately 10S cells) / tester) for 1 min with various concentrations (0,01-100 μM) of PDE inhibitors. , and an additional 4 min incubation with 1 μM prostaglandin E2. Ta. Five minutes after starting the reaction, lyse the cells by adding IM potassium carbonate. cAMP content was evaluated by RIA. General information about this assay A similar protocol is Radioiu+una by Brooker et al. ssay of cyclic AMP and cyclic GMP, A dv.

Cyclic Nucleotid, Res, 10: 1-33.197 9. The data are expressed as loribra obtained with 10 μM test compound. increased cAMP accumulation as a percentage of maximal response to rolipram. The EC6° is shown below. For the compound of the invention, the EC5o is 0.030 In the range from μM to >10 μM.

Effect of the compound of formula (1) on suppressing TNF production Human monocytes of the compound of formula (I) Inhibitory effect on TNF production in vitro by Effect of the compound of formula (1) on TNF production by human monocytes in vitro EP, Badger et al., February 6, 1991, O Publication Application Specification No. 0411 754A2 and Haunch (mouth anna) 19 According to the protocol described in WO90/15534 dated December 27, 1990 more measurable.

n, in vivo activity for compounds of formula (I) using two models of endotoxin shock. TNF activity was measured in vitro. Professionals used in these models Tocol is based on the EPO publication dated February 6, 1991 by Badger et al. Application No. 0 411 754 A2 and Hanna 199 It is described in Wo 90/15534 dated December 27, 2009.

When the compounds of this invention are administered according to the description of this invention, unacceptable toxicological No effects expected.

Next, the present invention will be explained with reference to Examples, but they are not intended to limit the compounds of the present invention. stomach.

3-Hydroxy-4-methquin-benzaldehy in Lumamide (0,25L) (40 g, 0.26 mol), potassium carbonate (40 g, 0.29 mol) and A mixture of lomon clobentane (32 ml, 0.31 mol) was added under an argon atmosphere. , heated at 100°C. After 4 hours, additional bromocyclopentane (8 ml, 0 ．． 08 mol) was added and heating continued for 4 hours. The mixture was cooled and filtered. filtrate Concentrated under reduced pressure and the residue was partitioned between ether and aqueous sodium carbonate. organic The extract was washed with aqueous sodium carbonate solution and dried (potassium carbonate). solvent Remove in vacuo and flash chromate the residue eluting with hexane/ether (2:1). Purified by chromatography to give a pale yellow oil of 3-cyclopentyloxy-4-methane. Oxybenzaldehyde (52g 189%) was obtained.

Elemental analysis: Calculated value (%) as C+sH+sOs: C, 70,89; H, 7 ゜32: Measured value (%): C, 70, 71; H, 7, 33; under argon atmosphere , 3-cyclopentyloxy-4-methoxybenzene in a solution of benzene (50 ml). Nzaldehyde (22.3 g, 101 mmol), dimethyl malonate (17 ml) , 101 mmol), Piverdine (0.5 mL 0.861 mmol) and A mixture of acetic acid (0.3 ml, 0.861 mmol) was added with azeotropic removal of water. Stir at reflux temperature. After 6 hours, the solvent was removed in vacuo and the residue was dissolved in ether and saturated carbonate. Partitioned between sodium and extracted. Dry the organic extract (potassium carbonate) Condensation gave the title compound (33.5 g, 100%) as an orange oil.

It was used without further purification.

c) 3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl) Methyl ropionate (3-fuclopentyloxy-4-methoxybenzylidene) Dimethyl malonate (33.5 g, 101 mmol) in methanol (250 ml) and potassium cyanide (6.7 g, 101 mmol) in water (5 ml). Processed. The mixture was heated to reflux. After 5 hours, the solvent was removed in vacuo and the residue was purified with ether. and sodium bicarbonate (5%) and extracted three times. Dry the organic extract The dried (potassium carbonate) and solvent were removed in vacuo. The remaining oil was diluted with 25-40% acetic acid. Purified by flash chromatography eluting with chill/hexane to give a white solid. The title compound (13.2 g, 43%) was obtained.

) Methyl propionate (6.0 g, 19.8 mmol) and 70% perchloric acid (1°95 ml) of 10% palladium on carbon (1°95 ml) in methanol (100 ml) 0.9 g) was added to the suspension. Hydrogenate the mixture for 1.5 hours at 50 psi. , diluted with methylene chloride, filtered through Celite and evaporated. Treat the residue with chloride Partitioned between tyrene and dilute aqueous sodium bicarbonate solution and extracted three times. organic layer Dry (potassium carbonate). Evaporation of the solvent gave the amine as a yellow oil (6,0 g , 100%) was obtained.

Methyl (4-methoxyphenyl)butyrate (6.0 g, 19.8 mmol) and A solution of a catalytic amount of sodium cyanide was refluxed for 20 hours. Remove solvent under vacuum to obtain a residue, which was partitioned between methylene chloride and water and extracted twice. Dry the organic layer Dry (potassium carbonate) and evaporate to a solid. Chloroform/methanol (95 Purified by flash chromatography eluting with :5) to give a solid (3.7 g .

67%). Melting point: 130°C.

The chiral separation of quinphenyl)-2-pyrrolidinone was carried out by E. Preparative HP of 8cm x 55cm column packed with 1.0kg of S. triacetate Performed using LC conditions (15-25m). Transfer of ethanol/water (95:5) The phase was eluted at a flow rate of 20 ml/min at an injection rate of Ig/30 ml at ambient temperature. . 254 nm was used for ultraviolet detection of the eluted product. The retention time is S - (10) 68 minutes for the isomer and 86 minutes for the R-(-) isomer, each , 88% (>99%ee) and 87% (>98%ee) recoveries.

The chiral mixture was prepared in dry dimethylformamide (10 ml) under an argon atmosphere. 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone (510 mg, 1.85 mmol) was diluted with sodium hydride for 45 minutes at room temperature. (62 mg of 80% dispersion, 2.04 mmol). Add bromide to the mixture. p-bromobenzyl (509 mg/2.04 mmol) in dimethylformamide A solution (1 ml) was added and stirred for 3 hours. Water was added and the mixture was washed with ether three times. Extracted.

The combined extracts were dried (potassium carbonate) and the solvent was removed under vacuum. Remove the residue by flash chromatography eluting with ether/methylene chloride (9:1). Purification gave the solid title compound (630 mg, 76.5%). Melting point 100-10 2℃.

Elemental analysis Calculated value (%) as C23H26NO3Br: C, 62, 17; H, 5,90; N, 3.15; Br, 17.98 Measured value (%): R-(=) C, 6 2,01;H,5,88;N,3.16S-(-)C,62,14;H,5 , 96; N, 3.16; Br, 18.21[a] 25o (cl, methanol ) = +50.4゜[a] 25o (cl, methanol) = -48.1゜actual Example 2 1-(benzyl)-4-(3-cyclopentyloxy-4-methquinphenyl) -24-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidi Non (689 mg, 2.5 mmol) was dissolved in dry dimethylformamide (12 ml). ), sodium hydride (90 mg, 3.0 mmol of 80% dispersion, in hexane) (washed 3 times) and stirred under an argon atmosphere. After 2.5 hours, bromide Benzyl (360 ml, 3.03 mmol) was added and the reaction mixture was heated at room temperature for 16 h. Stir for a while. Water was added to the reaction mixture and extracted with methylene chloride. organic extract Dry (potassium carbonate) and concentrate. With ether/methylene chloride (9:1) Purification by flash chromatography eluting the title compound as a pale yellow oil. (548 mg, 60.0%) was obtained.

Elemental analysis・C2s H27N On・1/2H20 Calculated value (%): C, 73,'77;H,7,54;N,3.74 Measured value (%):C,73,52;H ,7,18;N,3.72 Example 3 l-(4-carboxybenzyl)-4-(3-cyclopentyloxy-4-meth xyphenyl)-2-pyrrolidinone 1-(4-carboquinobenzyl')-4-(3-cyclopentyloxy-4-methyl Toxyphenyl)-2-pyrrolidinone 4-(3-pyrrolidinone produced in Example 1) Bentyloxy-4-methoxyphenyl)-2-pyrrolidone (200 mg 1 area 7 3 mmol) was added to a dry solution containing 15-crown-5-ether (100 ml). Sodium hydride (90 mg of 805 dispersion, 3 millimolar) suspension. Under argon atmosphere until gas evolution slows down. The suspension was stirred at room temperature and then heated at 50°C for 5 minutes to dissolve the sodium salt. I got the liquid. In a separate flask, add chloromethylbenzoic acid (183 mg, 1.08 mm mol) was dissolved in dry tetrahydrofuran (3 ml) and cooled to -78°C. n - Butyl lithium (2,5N solution 440ml 1.1.08 mmol) was added dropwise to the nucleic acid. and the solution was warmed to 0°C. Slowly add the sodium salt solution to the lithium salt of the nucleic acid. and the mixture was allowed to warm to room temperature. Pour the resulting solution into ice water and add 3M salt. Acidified with acid and extracted with methylene chloride. The organic extract was washed twice with water and dried ( sodium sulfate). The residue was dissolved in ether containing 1% acetic acid/methylene chloride (1: It was purified by flash chromatography eluting with 1). Solid markings The compound (94 mg, 32%) was recrystallized from ethanol/ether. Melting point 17 3.5-175.5°C.

Elemental analysis - Calculated value (%) as C24HztNOs: C, 70, 40; H, 6 , 65; N, 3.42 Measured value (%): c, 70.26: H, 7, 63, N, 3.40 Example 4 S-(-)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy- 4-methoxyphenyl)-2-pyrrolidinone a) S-(-)-1-(4-nitro benzyl)-4-(3-cyclobentyloxy-4-Lj'f'y phenyl)- 2-Pyrrolidinone S-(+)-4-(3-cyclopentyl) prepared in Example 1 Luoxo-4-methquinphenyl)-2-pyrrolidinone (1.8g, 6.5ml mol) in dry dimethyl fluoride containing 15-crown-5 ether (1,28 ml). Sodium hydride (196 mg, 80% dispersion in lumamide (65 ml)6. 53 mi! J mol) was added to the suspension. The suspension was heated at room temperature under an argon atmosphere. Stir overnight and then heat at 50-60"C for 90 minutes to obtain a solution of the sodium salt. Ta. 4-Nitrobenzyl bromide (2.79 g, 12.9 mmol) was added to dry tetrahydrogen Dissolved in Dorofuran (70ml) and added the sodium salt solution.

The reaction mixture was stirred overnight and the tetrahydrofuran was removed under vacuum. The obtained solution The liquid was poured into ice water, acidified with 3M hydrochloric acid, and extracted with ethyl acetate. organic extract Washed six times with water, dried (sodium sulfate) and evaporated under vacuum. the residue, Elute first with 1-2% methanol/chloroform, then ethyl acetate/hexane. Purified by two flash chromatography eluting with (3:1), The title compound (505 mg, 19%) was obtained as a yellow resin.

[al　D(0,61,methanol)=-48,5゜b)S-(-)-1-( 4-aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl) )-2-pyrrolidinone in anhydrous tetrahydrofuran (9 ml), 5-(-)- 1-(4-nitrobenzyl)-4-(3-cyclopentyloxo-4-methoxy A solution of phenyl)-2-pyrrolidinone (450 mg, 1.1 mmol) was dissolved in formic acid. Ammonium (1,04 g, 16.4 mmol) and 10% palladium/carbon (1.27 mg) in methanol (25 ml). the suspension at 3 o'clock Stir for a while. The reaction was then filtered through Celite and washed with methanol. . The solvent was removed under vacuum and the residue was partitioned between methylene chloride and water.

After extraction, the organic layer was washed twice with water, dried (potassium carbonate) and concentrated under vacuum. Shrunk. Elute the resin with a 50-75% gradient of ethyl acetate/methylene chloride. The title compound (3 42 mg, 81%) was obtained.

Elemental analysis・C23H211N203・115H! Calculated value as O (%) + (: , 71.92; H, 7,45; N, 7.29 Measurement ratio (%): C, 71,97; H , 7, 60; N, 7.28 [al 25. (0,63, methanol) = -72 ,5°・Example 5 R-(+)-1-(4-aminobenzyl')-4-(3-cyclopentyloxy -4-Metquinhue, nyl)-2-pyrrolidinone, sb 201158R-(+ )-1,-(4-nitrohensyl)-4-(3-cyclopentyloxy-4-methyl Toxyphenyl)-2-pyrrolidinone R-(-)-4- produced in Example 1 (3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone (1 81 mg, 6.57 mmol) and 15-crown-5 ether (1,28 m 1) Sodium hydride (20ml) in dry dimethylformamide (65ml) containing 2 mg, 80% dispersion). The suspension was stored in a room under an argon atmosphere. Stir overnight at room temperature and then heat at 50-60°C for 90 minutes to dissolve the sodium salt solution. I got it. 4-Nitrobenzyl bromide (2,79 g, 12.9 mmol) was dissolved in dry tet Dissolved in lahydrofuran (70ml) and added the sodium salt solution. reaction mixture The mixture was stirred overnight and the tetrahydrofuran was removed under vacuum. Place the resulting solution in ice water. It was acidified with 3M hydrochloric acid and extracted with ethyl acetate. Organic extract with water 6 times Washed, dried (sodium sulfate) and evaporated under vacuum. Residue, 1-3 Flash chromatography eluting with % methanol/chloroform Purification gave a yellow resin (570 mg, 21%).

[al　D(0,63, methanol)=+43.8°R-(+)-1-(4- aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone R-(+)-1-4 in anhydrous dihydrofuran (6 ml) -(4-nitrobenzylamino)-3-(3-cyclobentyloxo-4-meth A solution of (xyphenyl)-2-pyrrolidinone (503 mg, 1.23 mmol) , ammonium formate (1,2 g, 19 mmol) and 10% palladium/carbon (120 mg) in methanol (18 ml).

The suspension was stirred under argon for 2 hours. Filter the reaction through celite and Washed with tanol. The solvent was removed under vacuum and the residue was treated with cold water and diluted with methylene chloride. Extracted twice with The organic layer was washed twice with water, dried (potassium carbonate) and vacuum Concentrated below. Resin in 50-100% ethyl acetate/methylene chloride gradient The title compound was purified by flash chromatography eluting as a colorless oil. (396 mg, 82%) was obtained.

Elemental analysis: Calculated value (%) as CzsH2sNfOs・115H20・C, 71,92;)(,7,45;N,7.29 measured value (%)・C,71,99;H ,7,54;N,7.31 [al　'', (0,56, methanol) = +72. 5゜Example 6 l-(4-ace)amidobenzyl)-4-(3-cyclopentyloxy-4- (methquinophenyl)-2-virorinone 4-Amino-3-(3-sic) in chloroform (35 ml) under an argon atmosphere. methyl lopentyloxy-4-methoxyphenyl)butyrate (560 mg, 2.12 mmol) and 4-acetamidobenzaldehyde (346 mg, 2.12 mmol) A solution of 30 min. Distilled 10ml of chloroform and replaced with fresh solvent. After refluxing for an additional hour, the process was repeated. .

Cool the mixture, remove the solvent under vacuum, and redissolve the residue in tetrahydrofuran. Then a solution of anhydrous hydrochloric acid in ether (1.0M, 1.6ml) was added. the solution Evaporate to dryness, redissolve the residue in anhydrous methanol, cool in a water bath and evaporate into methanol. A solution of sodium borohydride (200 mg, 3.2 mmol) in a liquid was added. The mixture was stirred at room temperature for 2 hours, cooled with 10% ethyl acetate/ether and water. 5% sodium hydroxide and dry the organic layer (sodium sulfate). Ta.

The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water and extracted twice.

The organic layer was dried (sodium sulfate) and evaporated. 0-1% methanol/acetic acid Ethyl acetate/ethyl ethyl chromatography was performed, eluting with ethyl Purification by crystallization from ether gave the title compound as an off-white solid (415 mg, 46% ) was obtained. Melting point 116-118°C.

Elemental analysis: Calculated value (%) as CzsHsoN204・1/8HzO: C, 70,69; H, 7,18; N, 6.59 Measured value (%): C, 70,52; H, 6,95; N, 6.53 5- produced in Example 4 in dry pyridine (3 ml) (-)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy-4- A solution of methoxyphenyl)-2-pyrrolidinone (77 mg, 0.2 mmol) , at 0° C., with acetic anhydride (90 ml, 095 mmol) dropwise. Argon atmosphere The reaction was stirred under ambient air overnight and the solvent was removed under vacuum. Dissolve the residue in ethyl acetate. The residue was washed with cold hydrochloric acid, water, and 5% sodium bicarbonate, and then washed again with water. Yes The organic layer was dried (sodium sulfate) and evaporated under vacuum to give a residue with 0-2% Flash chromatography eluting with gradient methanol/ethyl acetate The title compound (85.5 mg, 100%) was obtained in the form of a resin.

Elemental analysis: C25H3ON204 ・Calculated value (%) as 1/H20: C, 70,32; H, 7,20; N, 6.56 Measured value (%): C, 70,14; H, 7,22:N, 6.51 [a'l 25p (0,49, methanol) = -56, In 8° dry pyridine (3 ml), R-(10)-1-(4- aminobennol)-4-(3-cyclopentyloxy-4-methquinphenyl) A solution of -2-pyrrolidinone (115 mg, 0.3 mmol) was added to acetic anhydride at 0°C. (125 ml, 13 mmol) dropwise. The reactants were mixed under an argon atmosphere. Stir overnight and remove the solvent under vacuum to obtain a residue, which was added to an O-2% gradient. Purified by flash chromatography eluting with methanol/ethyl acetate This gave the title compound (59.5 mg, 47%) in the form of a resin.

Elemental analysis: C! Calculated value (%) as 6H3゜N, o4・1/4H 0: C, 70,32; H, 7,20, N, 6.56 Measurement II (%): C, 70,28; H ,7,17;N,6.44[al　”-(0,46,methanol)=+56.9 'Example 9 1-[4-N-(N'-cyano-8-methyl-isothioureido)benzyl]- 4-(3-Fuclobentyloxy-4-methoxyphenyl)-2-pyrrolidinone 1-(4-aminobenzyl)- in pyridine (2.5 ml) under an argon atmosphere. 4-(3-Fuclobentyloxy-4-methoxyphenyl)-2-pyrrolidinone (219 mg, 0.59 mmol) and dimethyl N-cyanodithioiminocarbonate A solution of (90%, 194 mg, 1.19 mmol) was heated at reflux temperature for 3 h. Ta.

Cool the mixture, remove the solvent under vacuum and dilute with 40-75% ethyl acetate/methylene chloride. The residue was purified by flash chromatography eluting the title compound at , a pale yellow oil (139 mg, 49%) was obtained.

Elemental analysis: C26H3ON403S Calculated value (%) as 1/2HzO: C, 64,04; H, 6,41; N, 11.49; S, 6.57 Measured value (%) C, 64,09; H, 6,39; N, 11.15; S, 6.57 Argon atmosphere 1-[4-N-(N'-cyano-8-methyl-isothiol) in ethanol under atmospheric pressure. benzyl]-4-(3-cyclopentyloxy-4-methoxyphenyl) )-2-pyrrolidinone (100 mg, 21 mmol) was saturated with ammonia. The mixture was mixed and heated at 95° C. for 24 hours. Cool the mixture and remove the solvent under vacuum; Flash chroma eluting the title compound with 5% Impropatol/methylene chloride. The residue was purified by chromatography to give the title compound as a glassy solid (48.5 mg, 51.7%).

Elemental analysis Calculated value (%) as CzsH2eNsOs・1/2CDC13: C, 62,39; H, 5,99; N, 14.36 measurement value (% door C, 62,48: H, 6,06:N, 14.26 Example 11 1-[4-N-(ureido)benzyl]-4-(3-cyclopentyloxy-4 -methoxyphenyl)-2-pyrrolidinone 1-(4-amide) in acetic anhydride (glacial acetic acid/water (1:1)) under an argon atmosphere. Novenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2 - A solution of pyrrolidinone (350 mg, 1.05 mmol) was dissolved in sodium cyanate. 223 mg in 4 rnl of water, 3.4 mmol). room temperature After stirring for 30 minutes, the reaction was poured into ice water, extracted with methylene chloride, and diluted with water for 3 Washed twice and dried (sodium sulfate). The solvent was removed under vacuum and the residue was 7- Flash elution with 80% ethyl acetate/methylene chloride containing 10% methanol Purified by chromatography, recrystallized from methylene chloride/ether, and solidified. The title compound (258 mg, 58%) was obtained as a solid. Melting point 113-115.5℃ .

Elemental analysis Calculated value (%) as C24H29N304: C, 68,06; H, 6 , 90; N, 9.92 Measured value (%): C, 67, 70; H, 6, 89; N, 9. 95 Example 12 1-(4-dimethylaminobenzyl)-4-(3,4-dimethoxyphenyl)- 2-pyrrolidinone a) 3,4-dimethoxybenzene in toluene solution (100 ml) under argon atmosphere. Nzaldehyde (20.0 g, 120 mmol), dimethyl malonate (16.4 g.

120 mmol), Piverdine (0.3 ml, 0.517 mmol) and acetic acid (03 ml, 0.861 mmol) at reflux temperature with azeotropic removal of water. The mixture was stirred at a temperature of After 2 hours at reflux temperature and overnight at room temperature, the cyclohexane The mixture was cooled to 5° C. and filtered. Recrystallized from chloroform/hexane A solid (1), 9 g, 35%) was obtained which was used without further purification.

b) Methyl 3-noano-3-(3,4-dimethoxyphenyl)propionate (3 ,4-dimethoquinopenzylidene) dimethyl malonate (11,7 g, 42 mmol ) was dissolved in methanol (70 ml), and potassium noanide (2.7 g, 42 ml) was dissolved in methanol (70 ml). mol) and water (10 ml). The mixture was stirred under argon for 18 hours. Ta. The solvent was removed under vacuum and the residue was dissolved between ether and sodium bicarbonate (5%). The mixture was extracted with ethyl acetate six times. Dry the organic extract (sodium sulfate) The solvent was removed under vacuum to give a yellow oil (3 g, 29%).

C) Methyl 4-amino-3-(3,4-dimethoxyphenyl)butyrate 3-cyano -methyl 3-(3,4-dimethoxyphenyl)propionate (3.0 g, 12 mi) limole) and 70% perchloric acid (1,9 g) in methanol (100 ml). Added to a suspension of 10% palladium/carbon (0.6 g). 1.25 at 50psi The mixture was hydrogenated for an hour, diluted with methylene chloride and filtered through Celite. and evaporated. Partition the residue between methylene chloride and dilute aqueous sodium bicarbonate solution and the pH was adjusted to above 9 by adding sodium carbonate. Water phase with methylene chloride It was extracted three times and the combined organic phases were dried (potassium carbonate). Evaporate the solvent and the yellow The amine (3.0 g, 100%) was obtained as a colored oil.

2-pyrrolidinone 4-amino-3-(3 ゜4-Dimethoxyphenyl)methyl butyrate (1.0 g, 4.0 mmol) and 4 -Reflux a solution of dimethylaminobenzaldehyde (0.6 g, 4.0 mmol) The mixture was heated to a temperature that almost distilled off all the solvent. Add more chloroform, Reflux was performed again to distill off most of the solvent. Cool the mixture and remove the solvent under vacuum. The residue was redissolved in tetrahydrofuran and diluted with an ethereal solution of anhydrous hydrochloric acid (1 ,0M.

4.0 ml) was added. Evaporate the solution to dryness and redissolve the residue in anhydrous methanol. Cool in a water bath, add sodium cyanoborohydride (0.5 g, 8.0 ml) mol) solution was added. The mixture was stirred at 0 °C for 1 h, warmed to 20 °C and vacuum The residue was diluted with 25% ethyl acetate/ether and cooled with dilute sodium hydroxide. distributed between. The aqueous layer was extracted and the combined organic phases were washed with water and dried (with sodium sulfate). um) let it happen. The solvent was removed under vacuum and the residue was purified with a catalytic amount of sodium cyanide. The mixture was dissolved in toluene and refluxed for 7 hours. Remove the solvent under vacuum and dissolve the residue in ethyl acetate. and washed twice with water. The organic layer was dried (sodium sulfate) and evaporated. Ta.

Flash chromatography eluting with 75-100% ethyl acetate/hexanes Purification was performed to obtain the title compound (572 mg, 40%) in the form of a resin.

Elemental analysis Cz+H2sN20s ・1/3Hz and L/calculated value (%): C, 69,98+H, 7,46; N, 7.77 Measured value (%): C, 70,08; H, 7,34;N,7.72 Example 13 1-(4-acetamidobenzyl)-4-(3,4-dimethoxyphenyl)-2 -pyrrolidinone 4-Amino-3-(3,4-dimethoxyf) in chloroform under an argon atmosphere. methyl)butyrate (1,01 g, 4.0 mmol) and 4-acetamidobe A solution of nzaldehyde (0.65 g, 4.0 mmol) was heated at reflux temperature for 2.5 hours. Heated. Cool the mixture, remove the solvent under vacuum, and dissolve the residue in tetrahydrofuran. and an ether solution of anhydrous hydrochloric acid (1.0 M, 4.1 ml) was added. melt The liquid was evaporated to dryness, the residue was redissolved in anhydrous methanol, and the borohydride cyanide was dissolved. Sodium (0.50 g, 8.0 mmol) was added. The mixture was heated at 0°C for 1 hour. Stir for a while, warm to 20°C, concentrate under vacuum, and dissolve the residue in 10% ethyl acetate/ether. and cooled dilute sodium hydroxide. Extract the aqueous layer and combine the organic phase was washed with water and dried (sodium sulfate). Remove the solvent under vacuum and remove the residue. It was dissolved in toluene containing a catalytic amount of sodium cyanide and refluxed for 6 hours. under vacuum The solvent was removed and the residue was dissolved in ethyl acetate and washed twice with water. Dry the organic layer (sodium sulfate) and evaporated. In ethyl acetate/chloroform (1:1) , flash chromatography eluting with a gradient of 0.5-8% methanol. Purified by filtration and recrystallized from ethyl acetate/ether, labeled as a solid. The compound (445 mg, 30%) was obtained.

Elemental analysis Calculated value (%) as C2+H23NzCh・1/2H20: C, 67 ,01;H,6,43;N,7.44 Measured value (%):C,67,20;H,6, 59+N, 7.53 Example 14 Upper two stands upper two kettle 2e glyph 4-(3,4-shiJ I-±!phenyl)-2-pi Lorigis begging 4-Amino-3-(3,4-dimethoxyf) in chloroform under an argon atmosphere. methyl)butyrate (1,01 g, 4.0 mmol) and 4-nitrobenzua A solution of aldehyde (0.60 g, 4.0 mmol) was heated at reflux temperature for 2.5 h. Ta. Cool the mixture, remove the solvent under vacuum and redistribute the residue in tetrahydrofuran. Dissolve and add an ethereal solution of anhydrous hydrochloric acid (1.0M, 4ml). Evaporate the solution to dryness After solidification, the residue was redissolved in anhydrous methanol, cooled in a water bath and subjected to hydrocyanation. A methanol solution of sodium boron (0.50 g, 8.0 mmol) was added.

The mixture was stirred at 0 °C for 1 h, warmed to 20 °C and concentrated under vacuum to give a residue of 10 % ethyl acetate/ether and cooled dilute sodium hydroxide. water layer The extracted and combined organic phases were washed with water and dried (sodium sulfate). under vacuum The solvent was removed and the residue was flushed with 40-80% ethyl acetate/methylene chloride. The title compound (560 mg, 39%). Melting point 100-101°C.

Elemental analysis Methanol (20 ml) and anhydrous tet as Cl9H2ON205 1-(4-nitrobenzyl)-4-(3,4- dimethoxyphenyl)-2-pyrrolidinone (500 mg, 1.40 mmol) The solution was mixed with ammonium formate (1,06 g, 16.8 mmol) and 10% para Treated with dium/carbon (140 mg). The suspension was stirred for 2 hours under argon. Ta. The reaction was then filtered through Celite and washed with methanol. under vacuum The solvent was removed and the residue was partitioned between methylene chloride and water. After extraction, dry the organic layer. Dry (sodium sulfate) and concentrate under vacuum to give the title compound (303 mg, 64% ) was obtained.

Elemental analysis Calculated value (%) as Cl9H22N203.5/8H30: C, 67 ,59;H,6,94;N,8.29 Measured value (%):C,67,48:H,6, 90:N, 8.19 4-amino-3-(3 -Soclopenzaloxy-4-methquinphenyl)methyl butyrate (0.5 g, 1. 5 mmol) and 4-/methylaminobenzaldehyde (0.27 g, 1. A solution of 8'E rimole) was heated at reflux temperature for 25 hours. Cool the mixture and place under vacuum Remove the solvent with 7, redissolve the residue in tetrahydrofuran 1, and cool in a water bath. Then, a solution of anhydrous hydrochloric acid in ether (1.0M, 3.8ml) was added. Evaporate the solution to dryness Allow to solidify, then redissolve the residue in anhydrous methanol and remove the (0.43 g, 69 mmol) was added. The mixture was incubated at 0°C for 3 hours and at 5°C for 1 hour. Stir for 6 hours, warm to 20°C, concentrate under vacuum, and dissolve the residue in 10% ethyl acetate/nitrogen. -7. Extract the aqueous layer and combine between the cooled dilute thorium hydroxide The organic phase was washed with water and dried (sulfuric acid). Remove the solvent by emptying the The residue was dissolved in toluene containing a tactile amount of lithium chloride, and refluxed. did. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate and washed twice with water.

The organic layer was dried (sodium sulfate) and evaporated. 67-78% ethyl acetate/ Purified by Furanoyu chromatography eluting with hexane, the resinous Sakura 32 compounds (366 mg, 60%) were obtained.

Elemental analysis C, s 1432N Calculated value (%) as 203・1/4H20: C , 72,70; H, 7,93; N, 6.78 Measured value (%) Ic, 72.76; H ,7,80:N,6.741-(4-N-carbomethyoxyrubamamidebenzi )-4-(3-Cyclopene dry methylene chloride and N-methylmorpholine (7 0m1. ．． 0.64 mmol), 1-(4-aminobenyl)-4-(3-sil Clopentyloxy-4-methoxophenyl)-2-pyrrolidinone (0.2g, A solution of 0.53 mmol) was added with methyloxalyl chloride (54 mL) at 0°C. ．． 58 mmol) was added dropwise.

- After stirring overnight, further methyloxalyl chloride (108 ml) was added and the reaction The mixture was partitioned between a cold aqueous solution of sodium bicarbonate and methylene chloride, and the organic phase was separated. Washing with water and concentration under vacuum gave a crude solid of the title compound, which was divided into ethyl acetate/ Recrystallized from ether (210 mg, 85%). Melting point 134-136℃0 element Analysis C2aHaoN206・], /8H20 Calculated value (%): C, 66, 62; H, 6,50; N, 5.98 Measured value (%): C, 66,54; H16, 57;N, 1-(4-N-cal prepared in Example 17) in 5.95 methanol 4- A solution of methquinphenyl)-2-pyrrolidinone (95 mg, 0.2 mmol) , treated with finely divided lithium hydroxide-hydrate (26 mg, 0.6 mmol), Stirred for 15 hours under argon atmosphere. The solvent was removed under vacuum and the residue was dissolved in ice and 3N Added to a mixture of hydrochloric acid, the title compound (73 mg, 81%) precipitated as a white solid. . Melting point 167.5-170°C (decomposition).

Elemental analysis Cl9H22N203 5/8H20 and shite calculated value (%): C, 64 ,75;H,6,36;N,6.04 Measured value (%):C,64,83;H,6, 43; N, 6.02 1-(4-amino) in anhydrous pyridine (3 ml) under argon. benzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2- A solution of pyrrolidinone (200 mg, 0.53 mmol) was added to the methanesulfonyl It was treated dropwise with loride (60 ml, 79 mmol). 60% of the solution C. for 30 minutes, then heated at reflux temperature for 2 hours. The reactants are mixed with a water-cooled acid aqueous solution and acetic acid. Partitioned between ethyl and the organic layer was dried (sodium sulfate). Solvent under vacuum flash chromatography, eluting the residue with 75-90% ethyl acetate/hexanes. The title compound (107 mg, 44% ).

Elemental analysis: C24H3ON202S ・Calculated value (%) as 1/3H20: C ,62,05;H,6,65+N,6.03 Measured value (%):C,62,11;H ,6,62:N,6.044-amino-3-(3-7 clopentyloxy-4- methoxyphenyl)butyrate (1,57 g, 4.9 mmol) and 4-cal A solution of bomethoxybenzaldehyde (082 g, 5.0 mmol) was dissolved at room temperature. It was stirred overnight and the next day heated at reflux temperature for 2 hours. Cool the mixture and under vacuum The solvent was removed and the residue was redissolved in tetrahydrofuran and diluted with anhydrous hydrochloric acid in ether. solution (1.0M, 6.5ml) was added. The solution was evaporated to dryness and the residue was dissolved in anhydrous methane. Sodium cyanoborohydride (0,4 7 g, 7.4 mmol) was added. The mixture was stirred at 0 °C for 2 h and at 5 °C for 16 h. Hold for an hour, warm to 20°C, concentrate under vacuum, and cool the residue with methylene chloride. Partitioned between dilute sodium hydroxide. The aqueous layer was extracted with methylene chloride and the combined organic The phase was washed with water and dried (sodium sulfate). Remove the solvent under vacuum and remove the residue was dissolved in toluene containing a catalytic amount of sodium cyanide and refluxed overnight. under vacuum The solvent was removed and the residue was dissolved in ethyl acetate and washed twice with water. Dry the organic layer (sodium sulfate) and evaporated. Elute with 40-75% ethyl acetate/hexane The title compound (1) was purified as a solid by flash chromatography. , 1g, 53%) was obtained. Melting point 98-99°C.

Elemental analysis: Calculated value (%) as CzsH2eNOs: C, 70, 90; H, 6,90: N, 3.31 Measured value (%): C, 7 area 69; H, 6,89; N, 3. 35 In methylene chloride, 1-(4-methylthiobenyl)-4-(3-cyclopene Tyloxy-4-methquinophenyl)-2-pyrrolidinone (0.5 g, 123 min A solution of m-chloroberoxobenzoic acid (80%, 0.5%) was cooled to 0°C. 43 g.

24 mmol). The reaction was allowed to stir for 3.5 hours under an argon atmosphere. .

The reaction was diluted with methylene chloride, three times with saturated aqueous sodium bicarbonate solution and three times with water. Washed once with brine. Dry the organic layer (potassium carbonate) and remove the solvent under vacuum. Removal of gave the title compound (0.5 g, 92%), which foamed under vacuum.

Elemental analysis: C2aH2eNO3S ・Calculated value (%) as 1/2H20: C163,69:H,6,68;N,3.09;'S+7.08 measurement value ( %): C, 63,69; H, 6,42; N, 3.12: S, 6.91 Example 22 1-(3,4-enemethquinbenzyl)-4-(3-cyclopentyloxy-4- methoxyphenyl)-2-pyrrolidinone 4-Amino-3-cyclopentyloxy- in chloroform under an argon atmosphere Methyl 4-methoxyphenyl)butyrate (1.5 g, 4.9 mmol) and 3.4 A solution of benzaldehyde (0.85 g, 5.1 mmol) was heated to reflux. ℃ for 2 hours, then stirred at room temperature overnight. Remove the solvent under vacuum and remove the residue. Redissolve in tetrahydrofuran and add an ethereal solution of anhydrous hydrochloric acid (1.0M, 5ml ) was added. The solution was evaporated to dryness and the residue was redissolved in anhydrous methanol and dissolved in silica. Sodium borohydride (0.5 g, 8.0 mmol) was added. the mixture The mixture was stirred at room temperature for 45 hours and then diluted with ethyl acetate/ether (1:1) and 5% sodium hydroxide. Partitioned between thorium and organic layer dried (sodium sulfate). solvent under vacuum was removed and toluene and a catalytic amount of sodium cyanide were added to the oil. reactant The mixture was stirred at room temperature overnight and heated to reflux for 6 hours. The toluene was removed under reduced pressure and the remaining The oil was partitioned between methylene chloride and water. The organic layer was dried (sodium sulfate) . Flash chromatography eluting the residue with chloroform/methanol (95:5) Purification by chromatography gave the title compound (1.6 g, 75%) as an oil.

Elemental analysis Calculated value (%) as C24H3+NOs・]/4SiO: C, 68,16; H, 7,09; N, 3.18 measured value (%): C, 68,12: H, 6,96;N,3.05 Example 23 4-Amino-3-(3-cyclopentyl) in chloroform under an argon atmosphere. methyl xy-4-methoxyphenyl)butyrate (1.5 g, 4.9 mmol) and A solution of 4-methylthiobenzaldehyde (0.78 g, 5.1 mmol) was refluxed. Heated at room temperature for 2 hours, then stirred at room temperature overnight. Remove the solvent under vacuum and remove the residue was redissolved in tetrahydrofuran and added with an ethereal solution of anhydrous hydrochloric acid (1.0 M, 5 m 1) was added. The solution was evaporated to dryness and the residue was redissolved in anhydrous methanol and sieved. Sodium borohydride (0.5 g, 8.0 mmol) was added. the mixture The mixture was stirred at room temperature for 4.5 h and then diluted with ethyl acetate/ether (1:1) and 5% hydroxide. The organic layer was dried (sodium sulfate). Melt under vacuum The medium was stirred at the removal temperature overnight and then at room temperature for 6 hours. Toluene under reduced pressure was removed and the remaining oil was partitioned between methylene chloride and aqueous acid. Dry the organic layer (sulfuric acid sodium). Elute the residue with chloroform/methanol (98:3) It was purified by flash chromatography to give the title compound (1.7g) as an oil. , 85%).

Elemental analysis: Calculated value (%) as C2aH2eNO3S・1/4SiOz: C ,67,57;H,6,85+N,3.28 Measured value (%):C,67,42:H , 6, 82:N, 3.19 Example 24 1-(4-methylsulfonylbenzyl)-4-(3-cyclopentyloxy- 4-Sodium periodate (201 mg, 0.94 mmol) under argon atmosphere ) and water in a water-cooled solution of 1-(4-methylthiobenzyl)-4-(3-cyclo Pentyloxy-4-methoxyphenyl)-2-pyrrolidinone (352 mg, 0 ．． A solution of 86 mmol) in methanol (8 ml) was added. Bring the reaction mixture to room temperature. Warm and then stir overnight. Remove the solvent under vacuum and dissolve the residue in methylene chloride and water. and extracted three times. Dry the organic layer (potassium carbonate) and remove the solvent. , to give the title compound (370 mg, 71%) as an oil.

Elemental analysis・Calculated value as CztHuNO4S・1/4SiO2 (%C, 65 , 13; H, 6, 60; N, 3.16 Measured value (%): C, 65, 26: H, 6, 66:N, 3.14 Example 25 1-(2-acetamidobenzyl)-4-(3-cyclobentyloxo-4-methane) tonophenyl)-2-pyrrolidinone 4- in chloroform under an argon atmosphere Methyl amino-3-(3-cyclopentyloxy-4-methoxyphenyl)butyrate (05 g, 165 mmol) and 2-nitrobenzaldehyde (0,26 g.

A solution of 172 mmol) was heated at reflux temperature for 9 hours. Cool the mixture and place under vacuum The solvent was removed and the residue was redissolved in tetrahydrofuran and dissolved in an ether of anhydrous hydrochloric acid. Solution (1.0M, 1.72ml) was added. The solution was evaporated to dryness and the residue was washed with anhydrous methane. Dissolve again in tanol, cool in a water bath, and add sodium borohydroxide (0° 21 g, 33 mmol) in methanol was added. The mixture was heated at 5°C for 18 hours. Warmed to 20°C, concentrated in vacuo, and dissolved the residue in ether containing ethyl acetate. Partition between cooled dilute sodium hydroxide solution and dry organic layer (potassium carbonate) I let it happen. The solvent was removed under vacuum and the residue was dissolved in a solution containing a catalytic amount of sodium cyanide. The mixture was dissolved in ene and refluxed for 15 hours. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate. and water and washed the organic layer twice with water. Dry the organic layer (sodium sulfate ) and evaporated. The residue was eluted with ethyl acetate/hexane (1:1). Purification by flash chromatography gave the product (468 mg, 69%). .

b) 1-(2-aminobenzyl)-4-(3-cyclopentyloxy-4-meth xyphenyl)-2-pyrrolidinone methanol (20ml) and anhydrous tetra In hydrofuran (5 ml), 1-(2-nitrobenzyl)-4-(3-cyclope methyloxy-4-methoxyphenyl)-2-pyrrolidinone (0.47 g, 1. ammonium formate (0.95 g, 15.1 mmol) and 10% palladium/carbon (110 mg). The suspension was purged with argon. The mixture was stirred for 18 hours at a lower temperature. The reaction was then filtered through Celite and washed with methanol. Washed with water. Remove the solvent under vacuum and partition the residue between methylene chloride and ice water. Ta. After extraction, the organic layer was washed with water, dried (sodium sulfate) and concentrated under vacuum. A colorless oil (434 mg, 100%) was obtained.

C) 1-(2-acetamidobenzyl)-4-(3-cyclopentyloxy-4 -methoxyphenyl)-2-pyrrolidinone in dry pyridine cooled to 0°C, 1 -(2-aminobenzyl)-4-(3-cyclopentyloxo-4-methkinf) A solution of 2-pyrrolidinone (0.43 g, 1.14 mmol) was dissolved in anhydrous vinegar. Treated dropwise with acid (216 ml, 2.28 mmol). - After stirring overnight, the reaction mixture The compound was partitioned between aqueous water-cooled hydrochloric acid and ethyl acetate, the aqueous layer was extracted and the combined organic Wash the layers with aqueous hydrochloric acid, water, aqueous sodium bicarbonate and dry (sodium sulfate). I let it happen.

The solution was concentrated in vacuo to give the title compound (293 mg, 60%) as a foam.

Elemental analysis・C25H3°N20. Calculated value (%): C, 70,07; H, 7,21; N, 6.54 measurement fm (%): C, 70,07; H, 7,02; N, 6. Around 40 z53 = -2- pylori 2s? Chloroform under argon atmosphere Among them, 4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl) butylene methyl acid (0.5 g, 1.65 mmol) and 3-nitrobenzaldehyde ( 270mg.

A solution of 179 mmol) was heated at reflux temperature for 9 hours. Cool the mixture and place under vacuum The solvent was removed and the residue was redissolved in tetrahydrofuran and dissolved in an ether of anhydrous hydrochloric acid. Solution (1.0M, 1.65ml) was added. The solution was evaporated to dryness and the residue was washed with anhydrous methane. Redissolved in ethanol, cooled in a water bath, oxidized sodium borohydroxide (02 4 g, 38 mmol) in methanol was added. This mixture was heated at 5°C for 18 hours. Warmed to 20°C, concentrated in vacuo, and dissolved the residue in ether containing ethyl acetate. and cooled dilute sodium hydroxide solution and dry the organic layer (potassium carbonate ). The solvent was removed under vacuum and the residue was washed with a catalytic amount of sodium cyanide. It was dissolved in toluene and refluxed for 40 hours. Remove the solvent under vacuum and dissolve the residue in ethyl acetate. and water, and the organic layer was washed twice. Dry the organic layer (sodium sulfate) and evaporated. Fluorine the residue with 40-66% ethyl acetate/hexane. Purification by chromatography gave a yellow oil (0.44 g, 64%).

b) 1-(3-aminopencyl)-4-(3-sochlorobentyloxy-4-meth KiZ7” Sangori: 2-pyrrolidinone methanol (20ml) and anhydrous tetra In hydrofuran (5 ml), 1-(3-nitrobenzyl)-4-(3-ene clope ndyloxy-4-methquinphenyl)-2-pyrrolidinone (0.44 g, 1. A solution of ammonium formate (], , Og) and 10% palladium um/carbon (110 mg). The suspension was stirred for 2 hours under argon. . The reaction was then filtered through Celite and washed with methanol. under vacuum The solvent was removed and the residue was partitioned between methylene chloride and water. After extraction, dry the organic layer. Dry (strium sulfate) and concentrate under vacuum to give the title compound (403 mg) as a colorless oil. , 100%) was obtained.

c)], -(]3-acetamidobenzyl-4-(3-cyclopentyloxy- 4-Methoquinophenyl)-2-pyrrolidinone 1-(3 -aminobenzyl)-4-(3-fuclobentyloxy-4-methoxyphenyl )-2-pyrrolidinone (0.40 g, 1.06 mmol) was dissolved in acetic anhydride (2 00 ml, 2.12 mmol). - After stirring overnight, the reaction mixture is Partition between aqueous water-cooled hydrochloric acid and ethyl acetate, extract the aqueous layer and combine the organic layers with water. Washed with hydrochloric acid, water, aqueous sodium bicarbonate and dried (sodium sulfate). . The solution was concentrated under vacuum to give the title compound (332 mg, 69%) as a solid.

Melting point 145-146, 5°C.

Elemental analysis C25H3ON204 ・1/8H20 Calculated value (%): C, 70,69:H, 7,18:N, 6.59 measured value (%):C, 70,72:H, 7,27;N, 6.49-78°C in anhydrous methylene chloride Minobenzyl'I-4-(3-fuclopentyloxy-4-methoxyphenyl) -2-Pyrrolidinone (224 ml) solution in triflic anhydrous (106 ml, 63 mmol) was added dropwise. After 5 minutes, some starting material remains and Additional triflic anhydride (35 ml, 0.21 mmol) was then added. under vacuum Remove the solvent and extract the resin by partitioning it between aqueous sodium bicarbonate and ethyl acetate. I put it out. The organic layer was washed with cooled dilute aqueous acid, water and dried (sodium sulfate). I set it. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate/hexane (75:25). The title compound (13 3 mg, 46%).

Elemental analysis: Calculated value (%) as C24H2□N, O, F3S: (:, 56 ．． 24; H, 5, 31; N, 5.47 Measured value (%): C, 56, 54; H, 5, 62; N, 5.47 Sodium cyanide (13 mg, 0 ．． 27 mmol) of 1-(4-carphomethoxybenzene prepared in Example 20). 'I-4-(3-fuclobentyloxy-4-methoxyphenyl)-2- A methanol solution of pyrrolidinone (300 mg, 0.71 mmol) was cooled to 0°C. and saturated with ammonia. The reaction was slowly incubated at 50-55°C for a total of 6 days. and heated. The solvent was removed under vacuum to obtain the crude product, which was dissolved in 4-6% methanol. The white The title compound (174 mg, 60%) was obtained as a colored solid. Melting point 164-165°C.

Elemental analysis Calculated value (%) as Cz4HzsN204 C, 70, 57; H, 6, 91; N, 6.86 θ constant value (%): C, 70, 47; H, 6, 81; N, 6. 90 Example 29 1-(2,4-diaminobenzyl)-4-(3-cyclopentyloxy-4-methyl Tokitoxyphenyl)-2-pyrrolidinone in chloroform under argon atmosphere , 4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)butyric acid Methyl (1,52 g, 495 mmol) and 2,4-dinitrobenzaldehye A solution of (0.98 g, 5.0 mmol) was heated at reflux temperature for 2 hours. blend Cool, remove the solvent under vacuum and redissolve the residue in tetrahydrofuran. An ethereal solution of aqueous hydrochloric acid (1.0 M, 6.5 ml) was added. Evaporate the solution to dryness The residue was redissolved in anhydrous methanol and this solution, cooled in a water bath, was added with cyanide. Sodium borohydroxide (0.44 g, 7.0 mmol) was added. This mixture The mixture was stirred at room temperature for 15 h, concentrated under vacuum, and the residue was dissolved in ether containing ethyl acetate. and cooled dilute sodium hydroxide solution and dry the organic layer (potassium carbonate ). The solvent was removed under vacuum and the residue was poured into a solution containing a catalytic amount of sodium cyanide. It was dissolved in toluene and refluxed for 15 hours. Remove the solvent under vacuum and dissolve the residue in ethyl acetate. and washed twice with water. The organic layer was dried (sodium sulfate) and evaporated. I set it. Flash chromatography eluting the residue with 40-60% ethyl acetate/hexane. It was purified by chromatography and recrystallized from ethyl acetate to give a yellowish brown solid (1.09g, 48%). Melting point 125.5-127°C.

b) 1-(2,4-diaminobenzyl)-4-(3-cyclopentyloxy- 4-methoxyphenyl)-2-pyrrolidinone methanol (7 ml) and anhydrous 1-(2,4-dinitrobenzyl)-4 in tetrahydrofuran (2,5 ml) -(3-cyclopentyloxy-4-methquinphenyl)-2-pyrrolidinone ( 0.1 g, 0.22 mmol) was mixed with ammonium formate (0.4 g) and 1 Treated with 0% palladium on carbon (40 mg). The suspension was kept under argon for 2 hours. Stirred.

The reaction was then filtered through Celite and washed with methanol. under vacuum The solvent was removed and the residue was partitioned between chloroform and water. After extraction, dry the organic layer (potassium carbonate) and concentrated under vacuum. The residue was dissolved in 0-2% methanol/acetic acid. Purified by flash chromatography eluting with chill to give the title compound as a resin. (70 mg, 79%) was obtained.

Elemental analysis Calculated value (%) as Cx5Hx*N30s・0.29H20: C, 6 8,97+8. 7.44; N, 10.49 Measured value (%): C, 69,26; H , 7, 36; N, 10.09 Example 30 1-(4-oxyamitobennyl)-4-(3-cyclobenthyloxy-4-methane) quinphenyl)-2-pyrrolidinone Dimethoxy/ethylene glycol and N-methylmorpholine (200 ml, 1° 82 mmol), 1-(4-carboxycarbamidopencyl)-4-(3-cy Clopentyloxy-4-methquinphenyl)-2-pyrrolidinone (458 mg .

099 mmol) was added to isobutyl chloroformate (230 mL, 1.8 mmol). ) was processed. Condensate liquid ammonia (5 ml) in a separate flask and add To this was added Metquin ethylene glycol (10 ml). After about 10 minutes, Chloro Add isobutyl formate to the flask and add ammonia/ethylene glycol dimethyl A portion of the ether solution (approximately 2-5 ml) was added to the reaction flask. After 45 minutes, vacuum The solvent was removed under water and the residue was dissolved in chloroform, twice with cold aqueous acid and twice with water. Washed. The organic layer was dried (sodium sulfate) and concentrated under vacuum to obtain a resin; Then add a 70-100% gradient of ethyl acetate/methylene chloride and finally vinegar. Flash chromatography eluting with ethyl acid/methanol (99:1) More refined. The title compound (190 mg, 43%) was a white solid. Melting point 1 80-182℃.

Elemental analysis: Calculated value (%) as CzsIhsNsOs: C, 66,50; H, 6,47; N, 9.31 measured value (%): C, 66,66; H, 6,47: N, 9.57 Example 31 1-(2,4-diacetamidobenzyl)-4-(3-cyclopentyloxy- Example 29 1-(2,4-diaminobenzyl)-4-(3-cyclo Pentyloxy-4-methoxyphenyl)-2-pyrrolidinone (0.22 g, 0 A solution of 55 mmol) was treated dropwise with acetic anhydride (209 ml, 2.20 mmol). did. - After stirring overnight, the reaction mixture was partitioned between ice-cold aqueous hydrochloric acid and ethyl acetate. The aqueous layer was extracted and the combined organic layers were washed with aqueous hydrochloric acid, water, and aqueous sodium bicarbonate. Cleaned and dried (sodium sulfate). The solution was concentrated under vacuum to obtain a resin, which Flash chromatography eluting with methanol/ethyl acetate (1:99) The residue was purified by chromatography to give the title compound (167 mg, 63%) in the form of a resin.

Elemental analysis・C27H3s N　sOs・Calculated value (%) as 1/4H,O・ C, 66,99; H, 6,98; N, 8.68 Measured value (%): C, 66,73; H, 6,93; N, 8.52 Example 32 1-(4-anopencyl)-4-(3-cyclopentyloxy-4-methoxy Phenyl)-2-pyrrolidinone 4-Amino-3-(3-cyclobenthyl) in chloroform under an argon atmosphere. methyl xy-4-methoxyphenyl)butyrate (2.1 g, 6.8 mmol) and and 4-noanobenzaldehyde (1.1 g, 8.2 mmol) at room temperature. Stirred for 72 hours, then heated at reflux for 1.25 hours. Cool the mixture and The solvent was removed in vacuo and the residue was redissolved in tetrahydrofuran and diluted with anhydrous hydrochloric acid. solution (1.0M, 9.0ml) was added. Evaporate the solution to dryness and dry the residue. To this solution, which was redissolved in methanol and cooled to 0°C, was added sodium cyanide boron hydroxide. Thorium (06 g, 95 mmol) was added. This mixture was stirred at room temperature overnight, Partitioned between methylene chloride and cooled dilute sodium hydroxide. Extract the aqueous layer, The combined organic layers were washed with water and dried (potassium carbonate). Remove solvent under vacuum The residue was dissolved in ethyl acetate and washed twice with water. Dry the organic layer (sulfuric acid solution) ) and evaporated. Flash elution with 75% ethyl acetate/hexanes Purification by chromatography yielded the title compound (1.4 g, 44 kg) as a solid. Ta. Melting point 92-93°C.

Elemental analysis Calculated value (%) as C24H26N 20s: C, 73, 82:H , 6,71; N, 7.17 measured value (%) C, 73,78; H, 6,95; N, 7.12 Example 33 1-[4-(J-imidazo)benzyl]-4-(3-cyclopentyloxy-4 -methquinophenyl)-2-pyrrolidinone 4-Amino-3-(3-cyclopentyl) in argon atmosphere F and chloroform. Methyl xy-4-methquinophenyl)butyrate (0.46 g, 1.4 mmol) and and 4-(1-imidazo)benzaldehyde (0.29 g, 1.7 mmol). The liquid was heated at reflux temperature for 1 hour. Cool the mixture and remove the solvent under vacuum to remove the residue. was redissolved in tetrahydrofuran and dissolved in an ethereal solution of anhydrous hydrochloric acid (10M, 2.0 m1) was added. The solution was evaporated to dryness and the residue was redissolved in anhydrous methanol and dissolved in water. Cool in a bath and add sodium borohydroxide cyanide (0.15 g, 2.3 mmol). ) was added to the methanol solution. The mixture was warmed to 20°C for 1.5 hours. , 16 hours at 5° C. and concentrated under vacuum. The residue was diluted with methylene chloride and cooled. Partitioned between diluted sodium hydroxide. The organic layer was washed with water and dried (potassium carbonate ).

The residue after concentration was dissolved in toluene containing a catalytic amount of sodium cyanide, and the residue was dissolved for 24 hours. It refluxed for a while. Remove the solvent under vacuum and dissolve the residue in ethyl acetate and wash twice with water. did. The organic layer was dried (sodium sulfate) and evaporated. First, 2-10% gradient methanol/chloroform, then -=2% gradient Continuous flash chromatography using methanol/chloroform (water equilibrated with ammonium oxide and dried with potassium carbonate), The title compound (159 mg, 26%) was obtained as a brittle resin.

Elemental analysis Calculated value (%) as C26H29N303・1/2H20: C, 70 ,89;H,6,86;N,9.53 Measured value (%):C,70,91+H,7, 12;N, 9.29 Example 34 1-(4-hydroxybenzitree-4-(3-7 clobenthyloxy-4-meth) Quinophenyl)-2-pyrrolidinone 4-Amino-3-(3-cyclopentyl) in chloroform under an argon atmosphere. methyl xo-4-methquinphenyl)butyrate (2.1 g, 6.6 mmol) and A solution of 4-hydroxybenzaldehyde (0.94 g, 7.5 mmol) was refluxed. Heated at stream temperature for 15 hours. Cool the mixture, remove the solvent under vacuum, and drain the residue. Redissolve in trahydrofuran and add an ether solution of anhydrous hydrochloric acid (1.0M, 7.4 m1) was added. The solution was evaporated to dryness and the residue was redissolved in anhydrous methanol and dissolved in water. Cool in a bath, add sodium borohydroxide (0.55 g, 8.7 mmol) ) was added. The mixture was warmed to room temperature overnight, concentrated under vacuum, and the residue was dissolved in methyl chloride. and cooled dilute sodium hydroxide. Wash the organic layer with water and dry. Dry (sodium sulfate). The residue was purified with toluene containing a catalytic amount of sodium anhydride. The solution was dissolved in the tank and refluxed for 15 hours. Remove the solvent under vacuum and dissolve the residue in methane chloride. The solution layer was washed once with water twice. Dry the organic layer (potassium carbonate) , evaporate it. Fluorescence eluting with 50-90% ethyl acetate/hexane Purified from 1 column and crystallized from ethyl ether and labeled as a solid. The compound (934 mg, 37%) was obtained. Melting point 118-120°C.

Elemental analysis as C23HnNO4 Calculated value (%): C, 72,42; H, 7,13; N, 3.67 Measured (kou 96): C,72,33:H,7,17+N,3.59oxy-4-methquinophenyl) To a solution of methyl propionate (484 mg, i, 6 mmol) was added 70% perchlorine. acid (155 ml, 17 mmol) and 10% nano/um/'carbon (12 mg ) was added. The resulting mixture was hydrogenated at 50 ps i for 2 hours and the celite bed was filtered through. The filtrate was concentrated under vacuum. The solid residue was dissolved in methylene chloride and sodium carbonate. further washed with sodium bicarbonate and dried the organic layer. (sodium sulfate). Remove the solvent under vacuum and dissolve the residue in 7-methylformamide. Dissolve 2-4-2-(4-t-butquinecarbonylamino) in phenyl)ethyl acetate (503 mg, 1 nmol of L6), iodide + l-IJ 'Jum (240 mg, 0.32 mmol) and triethylamine (225 ml , 1.6 mmol). After stirring for 1 hour at room temperature under argon atmosphere , the residue was partitioned between ether and water and extracted several times. Dry the organic extract (sulfuric acid macerate) Gnesium) and evaporated. Flash chromatography eluting with ethyl acetate/hexane Purification by chromatography gave the product (718 mg, 77%).

4-[N-(4-t-butoxycarboxylic acid) in dimethylformamide (30ml) Bonylamino-1-carboethoxybenzyl)amine]-3-(3-cyclopene) Methyloxy-4-methquinphenyl)butanoate (1.8 g, 309 mmol) A solution of catalytic amounts of sodium cyanide and dimethylaminopyridine (3 78 mg, 31 mmol) and heated at 95-100°C for 20 hours. Applicable The reaction mixture was partitioned several times between ether and water, and the organic extract was dried (magnetic sulfate). (sium) and evaporated. Flash eluting with ethyl acetate/hexane (46) Purification by chromatography gave a yellow foam (840 mg, 49%).

0 ml), 1-[ethyl 2-(4-t-butquine carbonylaminophenyl) acetato]-4-(3-fuclopentyloxy-4-methoxyphenyl)-2- A solution of pylori/non (920 mg, 1 mmol) was cooled to 0°C and Luoro Vinegar) S! (20 mm) and stirred at room temperature for 24 hours. Carbonate the reactant Quench by adding solid sodium hydrogen and dilute the reaction mixture with methylene chloride and water. distributed between. The organic extracts were dried (potassium carbonate) and evaporated. acetic acid Purified by flash chromatography, eluting with chill/hexane (4.6). The product (647 mg, 86%) was obtained.

Elemental analysis Calculated value as C26H32N205/lH2O (%C, 66, 36 ; H, 7,28; N, 5.95 Measured value (%): C, 66,11; H, 6,89; N, 5.66 Example 36 1-[Ethyl 2-(4-acetamidophenyl)acetamido 4-(3-cyclo Pentyloxy-4-methoxyphenyl)-2-pyrrolidinone Methylene chloride (0 , 25ml), 1-[ethyl 2-(4-aminophenyl)acemetho]-4-( 3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone (53 , 4 mg, 0.12 mmol) was diluted with acetic anhydride (35 mmol, 0°36 mmol). The mixture was treated with a solution of 1 mL) in methylene chloride (1 ml) and pyridine (3 drops). Argo After stirring for 3 hours under a nitrogen atmosphere, the reaction mixture was dissolved in ethyl acetate/hexane (73) The title compound was purified by Furanoyu chromatography as an oil, eluting with (55.1 mg, 94%) was obtained.

Elemental analysis Calculated value (%) as C25H8+N20a: C, 68,00; H, 6 ,93;N,5.66 measured value (%)・C,67,91;H,7,18;N,5. 54 Example 37 1-[2-(4-acetamidophenyl)acetic acid]-4-(3-cyclobenthyl) xy-4-methquinophenyl)-2-pyrroline in nonethanol (5 ml) -[ethyl 2-(4-aminophenyl)acemetho]-4-(3-cyclobentyl Oxy-4-methoxyphenyl)-2-pyrrolidinone (212mg, 043ml) A solution of lithium hydroxide hydrate (55 mg).

129 mmol) and stirred for 1 hour. Remove the solvent under vacuum and soak the resin in water. and acidified with a 10% aqueous hydrochloric acid solution. Convert the product to methylene chloride/methanol (95.5), and the organic extract was dried (magnesium sulfate) and evaporated. The title compound (174 mg, 88%) was obtained.

Elemental analysis: c16) 1s. Calculated value (%) as N, O, 3/8H20: C, 65,98; H, 6,55; N, 5.92 measured value (%) C, 65,94: H, , 6,54:N, 5.79 Example 38 1-(4-aminothiocarbonylbenzyl)-4-(3-cyclopentyloxy -4-Methoquinphenyl)-2-pyrrolidinone Produced in Example 32 in a pressurized vessel 1-(4-cyanobenzyl')-4-(3-cyclopentyloxy-4-methyl methoxyphenyl)-2-pyrrolidinone (850 mg, 2.18 mmol) A solution of alcohol (25ml) was added to ammonium sulfide (23.9% solution, 15ml 153ml). treated with Rimol). The vessel was sealed and the reaction was stirred at 65-75°C for 1 hour. . The reaction mixture was concentrated under vacuum, water was added and the aqueous phase was extracted three times with methylene chloride. . The extract was washed twice with water, dried (sodium sulfate) and evaporated to a yellow residue. I let it happen. The residue was crystallized from ethanol/water. 60-75% ethyl acetate/salt Purified by flash chromatography, eluting with methylene chloride, followed by vinegar. Crystallization from ethyl acid/ethyl ether gave a yellow solid (682 mg, 74%). Obtained. Melting point 85.5-87.5°C.

Elemental analysis C24H2s N Calculated value (%) as 203S: C, 67,90; H, 6,65; N, 6.60 Measured value (%): C, 67,63; H, 6,81; N , 6.38 Example 39 1-(4-methylmercaptocarboiminobenzyl)-4-(3-cyclopentyl (4-methogynphenyl)-2-pyrrolidinone hydrochloride acetone (4m l) in Example 38, 1-(4-aminothiocarbonylbenzyl)-4-(3- Cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone (290m g, 0.68 mmol) was dissolved in methyl iodide (100 ml, 1°61 mmol). ) was processed. The reaction was stoppered and stirred at room temperature for 18 hours. ethyl ether In addition, the formation of a cream-colored solid was completed, which was extracted by filtration and dissolved in ether. Washed (336 mg, 87%). Melting point 170-172°C.

Elemental analysis: C25Hs. Calculated value as N203S-HI (%) C, 53,0 1; H, 5,52; N, 4.95 Measured value (%): C, 52,99; H, 5,51 ;N, 1-(4 produced in Example 39) in 4.68 ethanol (1.8 ml) -methylmercaptocarboiminobenzyl)-4-(3-cyclopentyloxy -4-methoxyphenyl)-2-pyrrolidinone hydrochloride (350 mg, 0.62 mmol) and ammonium acetate (151 mg, 1.95 mmol) was heated at 90-95°C for 1 hour under an argon atmosphere. Cool the reaction mixture The white crystals were collected and washed sequentially with methanol and ethyl ether (23 4 mg, 78%). Melting point 186-188°C.

Elemental analysis・C24H29N303・CzH40” Calculated value (%) as N20: C,64,31:H,7,26;N,8.65 Measured value (%):C,64,63: H,7,32;N,8.561-[4-(2-imidazo)benzyl]-4-(3 -cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone 1-(4-formamidiniumbenzyl)-4- of Example 40 in chloroform. (3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone/vinegar A solution of the acid salt (183 mg, 0.38 mmol) was dissolved in 10% sodium hydroxide and Treated with ice. This mixture was extracted with chloroform and the organic layer was dried (potassium carbonate and evaporated to a residue of formamidine. The residue was removed under an argon atmosphere. Dissolved in chloroform (20ml), chloroacetaldehyde (50% aqueous solution, 113ml (1.0.28 mmol) and triethylamine (119ml, area 86 mmol). The mixture was heated at reflux temperature for 5 hours and stirred at room temperature for 86 hours. Stirred. The solvent was removed under vacuum and the residue was subjected to flash chromatography. Purified and eluted with 0.5-1% methanol/chloroform. The residue was dissolved in ethyl acetate. /ethanol and extracted with cooled 10% aqueous hydrochloric acid. The acid extract was diluted with acetic acid. Washed 4 times with ethyl, the aqueous layer was made alkaline with an aqueous sodium carbonate solution, and the aqueous layer was made alkaline with aqueous sodium carbonate solution. The mixture was extracted three times using a lens. The combined methylene chloride phases are dried (potassium carbonate) and evaporated. A brittle resin (44 mg, 27%) was obtained.

Elemental analysis Calculated value (%) as CzsHzsN303・1/2H20: C, 70 ,89;H,6,86:N,9.54 Under argon atmosphere, tetrahydrofuran ( 15 mm) of Example 3, 1-(4-carboxybenzyl')-4-(3-cyclo Lopentyloxy-4-methoxyphenyl)-2-pyrrolidinone (225 mg, 0.62 mmol) was added to N-methylmorpholine (112 mL 1.02 mmol). rimol) was added dropwise. In a separate flask, add dimethylamine (15 ml) to - Bubble into a solution of dry tetrahydrofuran (15 ml) at 78°C. Next, nucleic acids and N-methylmorpholine in isobutyl chloroformate (135 ml, 10.2 mmol) and stirred for 7 minutes under an argon atmosphere. Mixed anhydride suspension The liquid was transferred via cannula to the flask containing the amine and the cooling bath was removed.

After 15 minutes, the reaction was concentrated under vacuum and partitioned between ethyl acetate and aqueous sodium carbonate. Arranged. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with water and dried (with sulfuric acid). sodium chloride) and evaporated. Elute with 4-6% methanol/ethyl acetate The resin (104 mg, 38%) was purified by fragrant chromatography. Ta.

Elemental analysis C28H32N Calculated value (%) as 204・115HzO: C, 7 0,95; H, 7,42+N, 6.36 measured value (%) C170,94; H, 7, 26; N, 6. 1- produced in Example 34 in pyridine (2 ml) at 10°C. (4-hydroxybennol)-4-(3-cyclopentyloxy-4-methoxo A solution of (239 mg, 0.63 mmol) Acetic anhydride (160ml.

17 mmol) and stirred for 72 hours under an argon atmosphere. reactant Poured into water-cooled aqueous hydrochloric acid and extracted twice with ethyl acetate. Cool the organic extract. Washed with hydrochloric acid, cold water and chilled aqueous sodium bicarbonate. Dry the extract ( sodium sulfate) and evaporated. Fluid eluting with 60% ethyl acetate/hexane The resin (148 mg, 55.5%) was purified by Rage chromatography. I got it.

Elemental analysis - Calculated value as CzsHleNOs (%): C, 70, 90; H, 6 ,90;N,3.31 Measured value (%):C,70,71;H,7,00;N,3. 25 Example 44 1-(4-acetamido-2-aminobenzyl)-4-(3-cyclopentyl) xy4-methoxyphenyl)-2-pyrrolidinonetrobenzyl)-4-(3- Cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone ethanol 1-(2,4-dinitrobenzyl)-4-(3 -cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone (426 mg, 0.94 mmol) was added to a suspension of 3 parts of ammonium sulfide (ethanol 1.67 g total, 5.9 mm total) for each addition. The mixture was then heated to reflux for 10 minutes, and then stirred at room temperature for 18 hours under an argon atmosphere. Ta. The solvent was removed under vacuum and the residue was purified by flash chromatography. Ta. Elute with 50-60% ethyl acetate/hexane, 2-amino-4-nitro isomer (140 mg, 35%) was obtained while dissolving in 70-90% ethyl acetate/hexane. Continued extraction gave the 4-amino-2-nitro isomer (180 mg, 45%).

b) 1-(4-acetamido-2-nitrobenzyl)-4-(3-soclopentyl) (4-methoxyphenyl)-2-birolinone Pyridine cooled to 0℃ 1-(4-amino-2-nitrobenzylbenzene)-4-(3-cyclobenzene) methyloxy-4-methquinphenyl)-2-pyrrolidinone (180 mg, 0. A solution of 42 mmol) was treated dropwise with acetic anhydride (105 ml, 11 mmol). .

The reaction was stirred at room temperature for 18 hours under an argon atmosphere. Cool the reactants with aqueous hydrochloric acid and extracted twice with ethyl acetate. The organic extract was diluted with cooled dilute hydrochloric acid, cold water and and washed with cooled aqueous sodium bicarbonate. Dry the extract (sodium sulfate) ) and evaporated. Flash chroma eluting with 60% ethyl acetate/hexane The resin was purified by chromatography to obtain a resin (200 mg, 100%).

and 1-(2-nitro-4-acetamide in tetrahydrofuran (3 ml) Bennol)-4,-(3-fuclobentyloxy-4-methquinophenyl)-2 - A solution of virolinone (814 mg, 0.42 mmol) in 10% radium /carbon and treated with ammonium formate (400 mg, 6.35 mmol) . The reaction was stirred under argon for 5 hours and then filtered through Celite. true Remove the solvent under vacuum and transfer the residue between cooled aqueous sodium carbonate and chloroform. This was distributed.

The organic extract was washed with water, dried (potassium carbonate) and evaporated. 75-1 00% ethyl acetate/methylene chloride elution chromatography method Purification was carried out by two additions, followed by recrystallization from heated ethyl acetate, and washing with ether. Orange crystals (35 mg, 20%) were obtained. Melting point 184-186°C.

Elemental analysis C25H31N304・1. /4H20 Calculated value (%): C, 6 7,93; H, 7,18; N, 9.51 Hori constant value (%): C, 68,08; H, 7,13;N, 9. 1-(2-A mino-4-nitrobenzyl)-4-(3-fuclopentyloxy-4-methoxy A solution of phenyl)-2-pyrrolidinone (140 mg, 0.33 mmol) was diluted with anhydrous It was treated dropwise with acetic acid (100 μL, 1.1 mmol). The reaction mixture was purged with argon. Stir for 24 hours at room temperature under atmosphere, then add 2 cycles of acetic anhydride (200 ml, 2.2 mmol; 400 μl, 44 mmol). Water-cool the reactants Poured into aqueous hydrochloric acid and extracted twice with methylene chloride. Cool the organic extract with dilute hydrochloric acid and cool Washed with water and 10% aqueous sodium hydroxide. Dry the extract (potassium carbonate ) and evaporated to give an oil (114 mg, 74%). 1-(2-acetamide -4-aminobenzyl)-4-(3-cyclobentyloxy-4-methoxyphene) Nyl)-2-pyrrolidinone. Methanol (10ml) and tetrahydrofuran (1,5 ml), 1-(4-nitro-2-acetamidobennru)-4-(3 -cyclopentyloxy-4-methquinophenyl)-2-pyrrolidinone (114 mg, 0.24 ml) of palladium/carbon (32 mg) and formic acid. Treated with ammonium (246 mg, 3.9 mmol). The reactants were evacuated with argon. Stir at room temperature for 4 hours, then filter through Celite. Remove the solvent under vacuum; The residue was partitioned between cold aqueous sodium carbonate and methylene chloride. organic extraction The effluent was washed with water, dried (potassium carbonate) and evaporated to form a glass (75 m g, 71%) was obtained.

Elemental analysis - Calculated value (%) as C25H31N304 - C,68,63:H, 7,14; N, 9.60 Measured value (%): C, 68,63; H, 7,25; N, 9 ．． 40 Example 46 1-[3-(2-chloroacetamido)benzyl]-4-(3-cyclopentyl Oxy-4-methquinophenyl)-2-pyrrolidinone at room temperature under argon atmosphere 1-(3-aminobenzyl)-4-(3-cyclopene) in dry acetone (4 ml). methyloxy-4-methoxyphenyl)-2-pyrrolidinone (0.23 g, 0.23 g, 6 mmol) and sodium carbonate powder (0,13 g.

chloroacetyl chloride (0.09 ml, 1.13 mmol) mmol) was added dropwise. After stirring for 4 hours, the solvent was removed under a stream of argon and the remaining The residue was partitioned between methylene chloride and ice water containing dilute hydrochloric acid. The aqueous layer was diluted with methylene chloride. The combined organic extracts were dried (sodium sulfate) and the solvent removed under vacuum. I left. Elute half of the residue with ether/methylene chloride: 1) Purify by chromatography and remove the remaining half with 45-60% ethyl acetate/method chloride. Purification by flash chromatography eluting with tyrene gave the title compound as a foam. (0.22 g, 80%) was obtained.

Elemental analysis Calculated value as C25HuCINzO (% C, 65, 71; H, 6 , 40:N, 6.13 Measured value (%): C, 65,72;8. 6.40; N, 5 ．． 99 Example 47 1-[4-(2-chloroacetamido)benzyl]-4-(3-chlorobentyl oxy~4-methquinphenyl)-2-pyrrolidinone 1-[4-(2-chloroa cetamido)benzyl]-4-(3-/clopentyloxy-4-methquinophene) Nyl)-2-pyrrolidinone Dry acetone (8 ml) at room temperature under argon atmosphere Among them, 1-(4-aminopencyl)-4-(3-cyclopentyloxy-4-meth xyphenyl)-2-virolinone (0.35 g, 0.92 mmol) and charcoal To a mixture of sodium chloride powder (0,195 g, 1.84 mmol) was added chlorochloride. Acetyl (0.132ml 1.1.66 mmol) was added dropwise. Stir for 1°5 hours. After that, the solvent was removed and the residue was partitioned between methylene chloride and ice water containing dilute hydrochloric acid.

The organic extract was washed twice with water, dried (sodium sulfate) and the solvent removed under vacuum. I left. Flash screen the residue with 45-60% ethyl acetate/methylene chloride. Purify by chromatography and triturate the product with ether to form a white solid. The title compound (0.35 g, 83%) was obtained. Melting point 138-139°C.

Elemental analysis - Calculated value (%) as C25H29CIN204: C, 65, 71; H, 6,40; N, 6.13 Measured value (%): C, 65,74: H, 6,36; N , 6.06 Example 48 Earth, two, two, two, two, two, two, two, two, three, three, three, two, three, three, two, three, three, two, three, three, two, three, three, two, two, two, three, two, two, two, three, two, two, two, two, two, two, two, two, two, two, two, two, two, two, two, two, two, two, two, two, three, three, two, two, three, three, two, two, three, three, two, three, two, three, two, three, two, two, three, two, two, three, two, two, two, two, two, three, two, two, two, two, two, two, two, two, two, two, two, two, two, two, two, one, three, three, two, two, two, three, three, two, two, three, two, two, two, three, two, two, two, three, two, two, two, two, three, three, two, two, two, three, three, two, two; -oxazolin-2-ylcarbonylamino)penzylco-2-pyro1-hydro xy-2-methyl-2-propylcarbamidecarbamide)benzyl-2-pyro Lysinone 1-(4-N-carboxylic acid) in alumina-treated chloroform (10 ml) methoxycarbamidebennol)-4-(3-cyclopentyloxy-4-methoxy) Cyphenyl)-2-pyrrolidinone (0,125 g, 0.27 mmol) , 2-amino-2-methylpropatur (0,051ml, 0.54mmol) was added and the mixture was stirred under an argon atmosphere overnight. Furthermore, 2-amino-2 - Add methyl propatool (0.037ml 1.0.27mmol) and stir for 8 It lasted for hours. The chloroform phase was extracted with dilute hydrochloric acid, washed with water and dried (natamine sulfate). Rium). Remove the solvent under vacuum and dissolve the residue in 2% methanol/chloroform. Purified by flash chromatography eluting with an oil (0,106 g.

79%).

Pyrrolidinone in dry methylene chloride (15 ml) at -45°C under argon atmosphere , in a solution of diethylaminosulfur trifluoride (0.054 mL 1.0.4 mmol), in dry methylene chloride (2.5 mL followed by 6 mL rinse) for 40 minutes. 4-(3-fuclopentyloxy-4-methoxyphenyl)” 1-(4-(N -1-Hydroxy-2-methyl-2-propylcarbamidecarbamide)benzyl A solution of co-2-pyrrolidinone (0.106 g, 0.2 mmol) was added dropwise. − After 75 min at 45°C, 5% aqueous sodium carbonate (5 ml) was added and the mixture was brought to room temperature. The organic layer was separated, dried (potassium carbonate) and evaporated. 2 residues Purified by flash chromatography, eluting with % methanol/chloroform. The title compound (0,071 g, 70%) was obtained as a resin.

Elemental analysis C2Q H3s Ns Calculated value as Os (%) C468,89; H, 6,98; N, 8.31 Measured value (%): C, 68,56; H, 6,94; N, 8.18 Example 49 4-(3-fuclopentyloxy-4-methoxyphenyl)-1-[4-(2- Oxazolin-2-ylcarbonylamino)penzylco-2-pyrrolidinone a) 4-(3-/Clopentyloxy-4-methquinol)-1-[4-(N- 2-Hydroquinoethyl carbamide carbamide benzyl]-2-pyrrolidinone al 1-(4-N-carbomethoxycarba) in chloroform (10 ml) treated with midobennol)-4-(3-cyclopentyloxy-4-methoxyphenyl)- A solution of 2-pyrrolidinone (0.185 g, 0.4 mmol) was added with ethanolamine. (0,049 ml, 0.81 mmol) and the mixture was placed under an argon atmosphere. Stir under air overnight. The solvent was removed under vacuum and the residue was dissolved in 2-3% methanol/chloromethane. The product was purified by flash chromatography, eluting with chloroform. Trituration with ether gave a white solid (0.175 g, 89%). Melting point 1 33-134℃.

Diethyl trifluoride in dry methylene chloride (15 ml) at -40°C under a Rougon atmosphere. in a solution of Ruaminosulfur (0,052ml, 0.39mmol) for 40 minutes. In dry methylene chloride (10 ml), 4-(3-cyclopentyloxy-4 -methoxyphenyl)-1-[4-(N-2-hydroxyethylcarbamidocal) solution of [bamidobenzyl]-2-pyrrolidinone (0.13 g, 0.26 mmol) was dripped. After 1 hour at -40°C, further diethylaminosulfur trifluoride (0 , 02 ml, 0.15 mmol) was added. After 1 hour, 5% aqueous sodium carbonate (4 ml) was added, the mixture was warmed to room temperature, the organic layer was separated and dried (potassium carbonate ) and evaporated. The residue was dissolved first in 20% acetone/methylene chloride and then in 2.5% acetone/methylene chloride. Continuous flash chromatography eluting with % methanol/chloroform The title compound (0.05 g, 40%) was obtained as a white solid. melting point 164-165℃.

Elemental analysis: Calculated value as C27H31N308 (% C, 67, 91; H, 6,54; N, 8.80 Measured value (%): C, 67,75; H, 6,53; N, 8 ．． 62 Example 50 4-(3-fuclopentyloxy-4-methoxyphenyl)-1-(4-bilba (midobenzyl)-2-pyrrolidinone 1-(4-Amino) in dry methylene chloride (7 ml) at room temperature under an argon atmosphere. pencil)-4-(3-cyclobentyloxy-4-methoxyphenyl)-2- Pyrrolidinone (0,183 g, 0.48 mmol) was added to pyruvoyl chloride (tetrachloride). A solution of 391% solution in carbon, 0.1 ml, 0.48 mmol) was added dropwise. 4 After stirring for an hour, the mixture was poured into a water-cooled 5% aqueous sodium bicarbonate solution and Extracted with tyrene three times. The organic extract was dried (sodium sulfate) and dissolved under vacuum. The medium was removed. The residue was diluted with 1-(4-aminobenzyl)-4-(3-cyclopentyl). 2-pyrrolidinone (54 mg, 0.12 mg) 20-25% ethyl acetate/method chloride. Purification was performed by flash chromatography, eluting with tyrene. Extract the product Trituration with ether gave the title compound (0.20 g, 72%) as a solid.

Melting point 95-97°C.

Elemental analysis Calculated value (%) as CzsH3oNzOs: C, 69, 31; H, 6 ,71;N,6.22:Measured value (%):C,69,02;H,6,59;N,6 ．． 29 The following compounds were prepared by the method described above.

Example 51 S-(-)-1-(4-amino-3,5-dimethoxybenzyl)-4-(3-one Clobentyloxy-4-methoxyphenyl)-2-pyrrolidinone resin.

Elemental analysis Calculated value (%) as C25Hs 2N20s・1/2H20: C, 71,91: H, 7,97: N, 6.71 Measured value (%): C, 71,88; H, 7,92; N, 6.57 Example 52 S-(-)-1-(4-acetamido-3,5-dimethoxybenzyl)-4-( 3-7 clobentyloxy-4-methoxyphenyl)-2-birolinone solid, Melting point 166-169℃: Elemental analysis: Calculated value (%) as CztHs4NzO4・1/4H20: C, 71,26; H, 7,64; N, 6.16 Measured value (%): C, 71,27, H, 7,54;N,6.04 Example 53 1-(4-aminobenzyl)-4-(3,4-bis-difluoromethoxyphenyl )-2-pyrrolidinone Resin body/ Elemental analysis・C19818F4N203・Calculated value (%) as 1/4H20: C ,56,65;H,4,63;N,6.95 measured value (%)・C,56,71;H , 4,62; N, 6.80 solid, melting point 131-132°C1 Elemental analysis Calculated value (%) as C21H20F4N204: C, 57, 27; H ,4,58;N,6.36 Measured value (%):C,57,15:H,4,64°N, 6.21 Resin body Elemental analysis Calculated value (%) as C21822F4N203・1/2H20: C, 57,9:3:H,5,32;N,6.48 Measured value (%):C,58,15;H ,5,16+N,6.31 Example 56 1-(4-acetamido-3,5-)methoxybenzyl)-4-(3,4-bis -difluoromethoquinphenyl)-2-pyrrolidinone resin body Elemental analysis Calculated value (%) as C23H24F, N2O4・1/21-120: C, 57,85; H, 5,28; N, 5.87 Measured value (%): C, 58,03; H, 5, 23; N, 5.69 Example 57 4-(3-noclobentyloxy-4-methoxyphenyl)-1-methoxymethy Ru-2-pyrrolidinone Ura Elemental analysis Calculated value (%) as C+ 8H2S N 04: C, 67, 69; H , 7,89; N, 4.39 Measured value (%): C, 67,50+8. 7.77:N , 4.34 Example 58 1-Benzoloxymethyl-4-(3-fuclobentyloxy-4-methkinf) E oil, Elemental analysis Calculated value (%) as 24 H2e N O4 1/41h○: C ,72,07+H,7,43;N,3.50 Measured value (%):C,71,93:H , 7, 28; N, 3.40 Example 59 Preparations for pharmaceutical use containing the compound of the present invention can be prepared in various forms with various excipients. It can be manufactured in

Preparations for inhalation The compound of formula 1 (1 μg to 100 mg) is aerosolized using a metered dose inhaler and used. Prevail the desired amount of drug per application.

Tablet/Ingredients 1 tablet 1. Active ingredient 40 mg (Compound of formula I) 24 corn starch 20 mg 3. Alginic acid 20 mg 4. Sodium alginate 2Q mglol, 3mg Operations regarding tablets Step 1 Components No. 1, No. 42, No. 3, and No. 014 are mixed in a suitable mixer/ Blend in blender.

Step 2 After adding each ingredient, carefully add enough water to the mixture from Step 1. Add. Add water and mix until the consistency where the mass turns into wet granules do.

Step 3: The wet mass is passed through a No. 8 mesh screen (2.38 mm). Convert into granules through a vibrating granulation device.

Step 4: The wet granules are then placed in an oven at 140'F (60°C) until dry. Dry with.

Step 5 Lubricate the wet granules with component No. 5.

Step 6: The lubricated granules are tableted using a suitable tableting press.

Parenteral preparation Pharmaceutical compositions for parenteral administration are prepared by combining a suitable amount of a compound of formula I with polyethylene glycol. It is manufactured by melting it while heating it. Then, this solution was converted to Ph, Eu r.

Dilute (to 100 ml) with water for injection. The solution was then diluted with 0.22 micron Sterilize by filtration through a membrane filter and seal in a sterile container.

Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number A61K 31/40 AED 31/415 ABY 7431-4CADY 7431-4C 311535A B D 7431-4CCO7D 207/27 Z 821 7-4C403/12 207 7602-4C413/12 207 760 2-4C (81) Designated episode EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IT, LU, MC, NL, SE), AT, AU, BB, BG, BR, CA, CH, C3, DE, DK, ES, F I, GB, HU, JP, KP, KR, LK, LU, MG, MN, M W, NL.

No, PL, RO, RU, SD, SE, USI (72) Inventor: Christensen, Siegfried Benjamin, The Four vinegar Raisto, Philadelphia, Pennsylvania 19103, United States REIT No. 2216

Claims (1)

[Claims] 1. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R1 is unsubstituted or substituted with one or more halogens C1-12 alkyl, unsubstituted or 1 to 3 methyl groups, or substituted with one ethyl group C3-6 cycloalkyl with one or two unsaturated bonds, C7-11 polycycloalkyl, (CR14R14)MC(O)-O-(CR14RH14)m-R10, ( CR14R14)nC(O)-O-(CR14R14)r-R11, (CR14R14)xOH, (CR14R1 4)sO(CR14R14)m-R10, (CR14R14)BO(CR14R14)r-R11, (CR14R14)n- (C(O)NR14)-(CR14 R14)m-R10, (CR14R14)n-(C(O)NR14)-(CR1 4R14)r-R11, (CR14R14)y-R11 or (CR14R14)r-R10 X1 is O or S; X2 is O or NR14; X3 is hydrogen or X: X is YR2, halogen, nitro, NR14R14 or formamide; Y is O or or S(O)m; R2 is -CH3 or -CH2CH3, each of which may be unsubstituted or substituted with 1 to 5 fluorines; R3 is hydrogen, halogen, CN, C1- 4 alkyl, halo substituted C1-4 alkyl, cyclopropyl unsubstituted or substituted by R9, OR5, -CH2O R5, -NR5R16, -CH2NR5R16, -C(O)OR5, C(O)N R5R16, -CH =CR9R9, -C≡CR9 or -C(=Z)H; R3' is hydrogen, halogen, C1-4 alkyl, halo-substituted C1-4 alkyl, unsubstituted cyclopropyl, -CH2OR5, -CH2NR5R16, -C(O)OR5, -C(O)NR5R16 or -C(=Z)H, substituted by ▼ (a) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (b) or (c) C1-3 alkyl unsubstituted or substituted with one or more fluorine or one or two R4 groups ; m is an integer of 0 to 2; n is an integer of 1 to 4; q is an integer of 0 to 1; r is an integer of 1 to 2; s is an integer of 2 to 4; x is an integer of 2 to 6; y is an integer of 1 to 6; z is an integer of 0 to 6; R4 is independently hydrogen, Br, F, Cl, -NR5R6, NR6R16, NO2, -C(Z)R7, -S(O) mR12, CN, OR16-OC(O)NR5 R16, 1- or 2-imidazolyl, -C(=NR16)NR5R16, -C (=NR5)-SR12, -OC(O)CH3, -C(=NCN) NR5R16, -C(S)NR5R16, -NR16-C(O)-R15, C(O)R15, oxazolyl, thiazolyl, pyrazolyl, triazolyl or tetrazolyl or when R5 and R16 are present as NR5R16, together with their nitrogen. Optionally, at least one further head selected from O, N or S. A 5- to 7-membered ring may be formed which may contain a terroratom; R5 is independently hydrogen or a C1-4 atom which is unsubstituted or substituted with 1 to 3 fluorines R6 is H, R12, -C(O)R12, -C(O)C(O)R7, -C(O)N R5R16, -S(O)mR12, -S(O)mCF3, -C(=NCN)SR12, -C(=NCN)R12, -C(=NR16)R12, -C(=NR16)SR12 or -C(=NCN)NR5R16; R7 is OR5, -NR5R16 or R12; R8 is hydrogen, C(O)R7, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl-[1,2,3 ), (3- or 5-triazoli -[1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxa (zolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxazolyl) Thadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]), (2-, 4- or 5-thiazolyl), (2 -, 4- or 5-oxazolidinyl), (2-, 4- or 5-thiazolidinyl) (2-, 4- or 5-imidazolidinyl); R9 is hydrogen, F or R12; R10 is hydrogen, methyl, hydroxy, aryl, halo-substituted aryl, aryl or oxyC1-3 alkyl, halo-substituted aryloxyC1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, furan, pyran, thiophene, thiopyran, C3-6 cycloalkyl, or one or two unsaturated bonds Yes C4-6 cycloalkyl, where the cycloalkyl and heterocyclic groups may be unsubstituted or substituted with 1 to 3 methyl groups or 1 ethyl group; R11 is unsubstituted or 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetrahydrofuran or 2-tetrahydrothiophene substituted with 1 to 3 methyl groups or 1 ethyl group; R12 is unsubstituted or 1 to 3 ethyl groups; C1-4 alkyl substituted with fluorine; R14 is independently hydrogen or C1-2 alkyl unsubstituted or substituted with fluorine; R15 is unsubstituted or one or more halogen; C1-4 alkyl substituted with, -C(O)C1-4 alkyl unsubstituted or substituted with one or more halogens, oxazolidinyl, oxazolyl, thiazolyl, virazo Lyle, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazo Lysinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl R16 is OR5 or R5; Z is O , -NR12, -NOR5, NCN, -N(-CN)2, -CRsNO2, -CR5C(O)OR12, -CRsC(O)NR5R5, -C(-CN)N O2, -C(-CN)C (O)OR12 or -C(-CN)C(O)NR5R5; however, (CR14R14)n-C(O)O-(CR14R14)m-R10, (CR14R14)n-(C(O )NR14)-(CR14R1 4)m-R10 or (CR14R14)■O(CR14R14)m-R10 When R10 is OH, m is 2, furthermore, q is O, and R3, R 3. When R8 and X3 are H, X is OR2, X2 is O, and X1 is O or S, at least one of the R4 or R14 groups in (a) or (b) is hydrogen. or a pharmaceutically acceptable salt thereof. 2. X1 and X2 are oxygen, A is (a), X is YR2, Y is O, and R1 is CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl, tetrahydrofuranyl, cyclopentenyl, C1-7 alkyl unsubstituted or substituted by one or more fluorine or chlorine, or -(CH2)2-4OH, and R2 is optionally 1 or more. C1-2 alkyl optionally substituted with more than one halogen, preferably fluorine or chlorine, one of R3 is hydrogen, the other of R3 is hydrogen, C≡CR9, CN, C(=Z) H, CH2OH, CH2F, CH2H or CF3, R3' is hydrogen, Z is O, NCN or NOR5, X3 is hydrogen, R4 is H, Br, OR16, CN, NR5R6, NO2, C (O)R7, S(O)mR12, 1- or 2-imidazolyl, -OC(O)CH3 or NHC (O)R15, and R8 is C(O)OH, H or C(O)OEt. The compound according to claim 1, wherein R14 is hydrogen, CH3, NH2 or NHC(O)CH3. 3. C1-4 alkyl, CH2-cyclopropyl, CH2-cyclopentyl, cyclopentyl or cyclopentyl, in which R1 is substituted by one or more fluorine is lopentenyl, and R2 is methyl or fluoro-substituted C1-2 alkyl. and R3 is hydrogen, C≡CH or CN, and R4 is hydrogen, Br, NH2, - NHC(O)CH3, C(O)OH, NHC(NCN)SCH3, NHC(O) NH2, N( CH3)2, NHC(O)C(O)OCH3, NHC(O)C(O )OH, NHS(O)2-CH3, C(O)OCH3, S(O)2CH3, SC H3, NHC(O ) C(O)CH3, S(O)CH3, NHC(O)C(O)NH2, CN, C(O)NH2, NHS(O)2CF3, C(NH)NH2, O- C(O) CH3, -C(O)N(CH3)2,1- or 2-imidazolyl, -NHC(O)CH2C1, -NHC(O)-oxazolidinyl, -NH-C(O)-4,4-dimethyloxazoli 2. A compound according to claim 1, which is di-niyl or OH. 4. R1 is cyclopentyl, CF3, CH2F, CHF2, CF2CHF2, CH2CF3, CH2CHF2, CH3, CH2-cyclopentyl, CH2-cyclo lopropyl or cyclopentenyl, R2 is CF3, CHF2 or CH2CHF2, one of R3 is hydrogen, the other of R3 is hydrogen, C≡CH or CN in the 4-position, and one of R4 is hydrogen and the other is -NHC(O)CH3, NH2, NH-C(=NCN)SCH3, NHC(O)CO2CH3, C(O) OCH3, NHC(O)NH2, NHC(O)C(O)CH3 or NHC(O2)C(O)NH2, or both R4 groups are NH2 or NHC(O)C2H3, R8 is hydrogen and R14 is hydrogen. 5. (S)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidinone; (R)-1-(4-acetamidobenzyl)-4-(3-cyclopentyl oxy-4-methoxyphenyl)-2-pyrrolidinone; (S)-1-(4-acetamidobenzyl)-4-(3-cyclo Pentyloxy-4-methoxyphenyl)-2-pyrrolidone; (R)-1-(4-acetamidobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl) 1-(4-oxyamidobenzyl)-4-(3-pyrrolidone); Clopentyloxy-4-methoxyphenyl)-2-pyrrolidinone; 4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(2,4-diacetaminone) dobenzyl)-2-pyrrolidinone; 4-(3-cyclopentyloxy-4-meth) xyphenyl)-1-(2,4-diaminobenzyl)-2-pyrrolidinone; 1-(4-carbomethoxybenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone; 4-(3 -cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methylisothio ureido]benzyl)-2-pyrrolidone; 1-(4-N-carbomethoxycarba 4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(4-N-[ureido]benzyl)-2- Pyrrolidone: and 4-(3-cy 2. A compound according to claim 1 selected from the group consisting of clopentyloxy-4-methoxyphenyl)-1-(4-pyruvamidobenzyl)-2-pyrrolidinone. 6. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier. 7. For use in inhibiting tumor necrosis factor (TNF) production or preventing TNF-mediated diseases. 6. A compound according to any one of claims 1 to 5. 8. 6. A compound according to any one of claims 1 to 5 for use in inhibiting phosphodiesterase IV. 9. The method according to claims 1 to 5 for use in treating allergic and inflammatory diseases. Any one compound. 10. Use of a compound of formula (I) according to claim 1 in the manufacture of a medicament for the inhibition of tumor necrosis factor (TNF) production or for the prevention of TNF-mediated diseases. 11. Use of a compound of formula (I) according to claim 1 in the manufacture of a medicament for the inhibition of phosphodiesterase IV. 12. Use of a compound of formula (I) according to claim 1 in the manufacture of a medicament for the treatment of allergic and inflammatory diseases. 13. (a) Formula (7): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R19 is H, R17 is an alkyl or aryl group, and R3' is H, R12 or unsubstituted or substituted with R9. and R1, X2, X and X3 are the same as described in formula (I) or modified into such groups. is a group that can be converted] with a suitable aldehyde, and then the imine is reduced to obtain a compound of formula (7) (R19 is CH2(CH2)mA), which is Sara or (b) a compound of formula (7) (R19 is H), with or without a catalyst, is cyclized to give a compound of formula I; or ( c) Cyclize the compound of formula (7) (R19 is H) to obtain a compound represented by formula (8): ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R19 means H] It is further reacted with a strong base, followed by a suitable activation atom. (d) react with a compound of formula (I) or (d) a compound of formula (7). In the case of a compound (R19 is H, R3 is CONH2), the compound is first protected at R19 using an appropriate protecting group, then subjected to amide dehydration, and then the protecting group is removed to obtain the formula (7). A compound (R19 is H, R3 is CN) is obtained which is then cyclized to form a compound of formula (I) (R3 is CN, X and X3 are S(O)mR2, Br, I, NO2 or or (e) in the case of a compound of formula (I) (R3 is OR5), a compound of formula (7) (R19 is H, R3 is protected or unprotected); or (f) compound (R3 is F), the compound of (e) can be further treated with diethyl trifluoride, trifluorominosulfur, or the desired or (g) a compound of formula (I) (R 3 refers to the remaining group of formula (I)) by protecting the amide or other sensitive functional group to obtain a compound of formula (I). ) or (8) (R3 is CN), then reducing the CN group of R3 to CHO, and then further converting the CHO group to a desired group to obtain a compound of formula (I). A process for producing a compound of formula (I) according to claim 1.